
==== Front
Biomark Res
Biomark Res
Biomarker Research
2050-7771
BioMed Central London

39227959
630
10.1186/s40364-024-00630-9
Review
Infiltrating treg reprogramming in the tumor immune microenvironment and its optimization for immunotherapy
Zhou Zhaokai 12
Xu Jiaxin 13
Liu Shutong 1
Lv Yingying 4
Zhang Ruiqi 1
Zhou Xing 5
Zhang Yuyuan 1
Weng Siyuan 1
Xu Hui 1
Ba Yuhao 1
Zuo Anning 1
Han Xinwei fcchanxw@zzu.edu.cn

167
Liu Zaoqu liuzaoqu@163.com

1678
1 https://ror.org/056swr059 grid.412633.1 Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 China
2 https://ror.org/056swr059 grid.412633.1 Department of Urology, The First Affiliated Hospital of Zhengzhou University, Henan, 450052 China
3 https://ror.org/04ypx8c21 grid.207374.5 0000 0001 2189 3846 Department of Human Anatomy, School of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001 China
4 https://ror.org/056swr059 grid.412633.1 Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 China
5 https://ror.org/056swr059 grid.412633.1 Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052 China
6 https://ror.org/04ypx8c21 grid.207374.5 0000 0001 2189 3846 Interventional Institute of Zhengzhou University, Zhengzhou, Henan 450052 China
7 grid.412633.1 0000 0004 1799 0733 Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, Henan 450052 China
8 grid.506261.6 0000 0001 0706 7839 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730 China
4 9 2024
4 9 2024
2024
12 9723 5 2024
31 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Immunotherapy has shown promising anti-tumor effects across various tumors, yet it encounters challenges from the inhibitory tumor immune microenvironment (TIME). Infiltrating regulatory T cells (Tregs) are important contributors to immunosuppressive TIME, limiting tumor immunosurveillance and blocking effective anti-tumor immune responses. Although depletion or inhibition of systemic Tregs enhances the anti-tumor immunity, autoimmune sequelae have diminished expectations for the approach. Herein, we summarize emerging strategies, specifically targeting tumor-infiltrating (TI)-Tregs, that elevate the capacity of organisms to resist tumors by reprogramming their phenotype. The regulatory mechanisms of Treg reprogramming are also discussed as well as how this knowledge could be utilized to develop novel and effective cancer immunotherapies.

Keywords

Tumor immune microenvironment
Tumor-infiltrating tregs
Reprogramming
Immunotherapy
The Henan Provincial Science and Technology Research Project221100310100 221100310100 issue-copyright-statement© Yumed Inc. and BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcIntroduction

In recent years, the application of immunology in oncology treatment has risen, mainly facilitating the immune responses against tumors by targeting the immune cell regulatory pathway in tumor immune microenvironment (TIME). For instance, immune checkpoint blockades (ICBs) have been demonstrated to be effective in a fraction of patients, but only a minority achieve long-term clinical efficacy (Fig. 1A). Individuals with ‘cold’ tumors, in which the immune system is minimally activated, have shown poor response rates and little benefit from ICBs. In “cold” tumors, regulatory T cells (Tregs) and tumor associated macrophages (TAMs) dominate the niche, forming a suppressive TIME through inhibiting anti-tumor immune activities [1, 2]. (Fig. 1B, C). The degree of response to ICBs is based on the type of TIME. Currently, according to mouse and human data, TIME is defined as three broad classes: immune-activated, immune-defected and immune-exempted, each characterized by distinct cellular compositions. Specifically, the highest levels of Tregs form part of immune-exempted TIME inhibiting the response of immunotherapy [3].

Fig. 1 Immune checkpoint blockades (ICBs) and Tumor immunosuppressive microenvironment. A. ICBs are extensively utilized in the management of a wide range of cancer types. B. Tumor immune microenvironment including various immune cells, tumor-associated inflammatory factors, immunosuppressive molecules and extracellular matrix, often causes patients with ‘cold’ tumors, thereby developing resistance and relapse to ICBs. C. Cellular crosstalk between Treg and immune cells. ICBs, Immune checkpoint blockades

Tregs, belonging to a specialized CD4+ T cell subpopulation, accumulate in tumors and are overactivated in diverse carcinomas to maintain immune tolerance and homeostasis and to hinder effective anti-tumor immunity [4–6]. Tregs facilitate immune escape in tumors through various mechanisms. These include the secretion of suppressor cytokines such as IL-10, TGF-β, and IL-35, as well as the inhibition of CD8+ T cell and dendritic cell (DC) functions via the binding of TGF-β and/or T cell receptors [7–9]. Tregs also upregulate checkpoint receptors like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), Lymphocyte Activation Gene-3 (LAG-3), and programmed death receptor 1 (PD-1), which can induce dormancy in memory T cells [10]. Additionally, they can kill effector cells through granzyme-mediated mechanisms. Tregs further inhibit the proliferation, interferon (IFN)-γ production, degranulation, and cytotoxicity of classical natural killer (NK) cells [11, 12]. This Treg-mediated inhibition is associated with the downregulation of T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and the upregulation of the inhibitory receptor PD-1, as well as IL-1R8—an IL-1 receptor family member—on classical NK cells. Furthermore, Tregs impact effector cell function by interfering with cellular metabolism, contributing to a more immunosuppressive tumor microenvironment [13]. Among Foxp3+ Tregs, there are two distinct subsets: central Tregs (cTregs) and effector Tregs (eTregs) [14]. Unlike cTregs, eTregs exhibit an effector-like phenotype and possess a more potent immunosuppressive capacity with significantly increased amounts of proteins that are necessary for the maintenance and suppressive activity, such as inducible co-stimulator, killer cell lectin-like receptor G1 (KLRG1), CTLA-4, and CD4415. The accumulation of Tregs (especially eTregs) within tumors represents a major obstacle to developing effective anti-tumor immunity. Besides, Tregs could also be divided into different subpopulations with natural Tregs (nTregs) and induced Tregs (iTregs) [16–19]. Stimulation within the tumor environment can prompt the transformation of naïve CD4+ T cells into ‘inducible’ Tregs [20]. As tumors progress, Tregs are recruited or induced. Specific inhibition of this subset represents a powerful approach to supporting anti-tumor response. Certain researchers have employed ablation of Foxp3+ Tregs to arouse tumor-antagonizing immunity, which was frustratingly devoid of clear translational potential and had diverse adverse effects [21, 22]. Therefore, expectations for Treg reprogramming which is defined as the lack of immunosuppressive function (also referred to as Treg destabilization) and/or the acquisition of pro-inflammatory or immunostimulatory properties are raised [23]. Recently, Pilato et al. described the reprogramming of Tregs to synthesize IFN-γ in an attempt to enhance immune checkpoint inhibitor therapy [24]. Tregs are highly plastic and heterogeneous cell populations influenced by exogenous and endogenous factors. Important endogenous factors are aberrant transcription, whereas exogenous factors are cytokines and DCs in TIME. Here, we will summarize the various factors and pathways that cause tumor-infiltrating Treg (TI-Treg) reprogramming to guide cancer immunotherapy (Fig. 2).

Fig. 2 The factors to reprogram TI-Tregs. Treg reprogramming is facilitated by a multitude of factors, such as different transcription factors, receptors, cytokines, and others. Firstly, transcription factors induce a series of signature genes in Tregs. Their alteration causes dysregulation of gene expression and thus impairs Treg function. A portion of receptors are essential for the development, stable inhibition of Tregs, and activation or inhibition of receptors induces alterations in downstream molecular signaling thereby reprogramming Tregs. CBM is an important mediator of immune signaling, downstream of the BCR/TCR, and constitutive disruption of any of its components hinders the development of thymic Tregs, as well as the inhibitory function of mature Tregs. Non-coding RNA interactions with transcription factors define the repressive activity of Tregs. The presence of inflammatory cytokines destabilizes tumor-associated Tregs. DCs affect Treg function by triggering IL-6 expression and homologous interactions with MHC II molecules. CBM, CARMA1-BCL10-MALT1 (CBM) signalosome complex; BCR/TCR, B cell receptor/T cell receptor; DCs, Dendritic cells

Treg depletion

In contrast to reprogramming Tregs to switch their phenotype and reduce their suppressive function, Treg depletion refers to the induction of systemic or local death of Tregs by various therapeutic approaches, thereby effectively reducing or eliminating the number of Tregs. In this therapeutic strategy, anti-CD25 antibodies are typical agents used to remove Tregs in mouse models, as they can block the IL-2 signalling pathway by binding to CD25, leading to Treg death [25, 26]. Recombinant immunotoxins (RITs), such as denileukin diftitox (Ontak, a protein that binds IL-2 and diphtheria toxin) and scFv-psm-ETA, can also cause massive Treg death. However, the use of RITs to deplete Tregs has strong side effects, as this therapy also affects CD4+ CD25hi effector T cells, further weakening the body’s anti-tumor immunity and increasing the patient’s risk of developing autoimmune diseases [25, 27].

Additionally, T cell receptor (TCR) signalling molecules in Tregs and conventional T cells (Tconv) are under different degrees of control, so another potential strategy is to target TCR signalling molecules. For example, ZAP-70 is specifically inhibited in Tregs upon TCR activation. Therefore, targeting ZAP-70 may selectively reduce TCR signalling, leading to selective death of Tregs, especially eTregs, due to apoptosis induced by signal deprivation [28]. Meanwhile, some chemotherapeutic agents may deplete Tregs by reducing their proliferation. Cyclophosphamide alkylates DNA, leading to DNA cross-linking and cell death to remove Tregs, while enhancing the efficacy of DC vaccines in melanoma or colon cancer mouse models [29, 30]. Vincristine inhibits DNA synthesis and inhibits the proliferation of IL-10-secreting Tregs in vitro, while promoting antigen-specific (CTLs) [31, 32]. Low-dose gemcitabine selectively inhibits TI-Tregs, reducing their numbers [33].

Although Treg depletion enhances the anti-tumor immune response to some extent, it has been accompanied by the major drawback of severe autoimmunity. In experimental models, systemic Treg depletion releases a strong anti-tumor response but also leads to severe morbidity. Therefore, once initiated, it seems challenging to control the autoimmune response triggered by systemic Treg depletion in patients [34, 35]. In contrast to Treg ablation, TI-Treg reprogramming may be tumor-specific and will not trigger systemic autoimmunity by interfering with the role of Tregs in maintaining peripheral homeostasis, thus reducing the incidence of immune-related adverse events. In addition, it has a number of other advantages. First, since the TCR profile of Tregs is biased towards recognition of self-antigens, reprogrammed Tregs can recognize self-antigens expressed by tumor cells without the need for new antigenic epitopes, as is the case with CTLs. Secondly, unlike CTLs, Tregs are abundant in TIME and a strategy to induce Treg conversion to effector cells would generate a large number of anti-tumor effector cells from existing Tregs that already recognize tumor self-antigens [36–38].

Alterations in intrinsic targets in TI-Tregs lead to reprogramming

Regulation of transcription factors in the TI-Tregs

Intracellular components, including various proteins, nucleic acids, cytokines, etc., are involved in regulating the stability of immunosuppressive Tregs, most notably changes in transcription factors [39] (Fig. 3). Transcription factors are DNA-binding proteins that specifically interact with the cis-acting elements of eukaryotic genes [40] and induce a series of signature genes in Tregs (Fig. 4A).

Fig. 3 Signals and pathways critical for the reprogramming of TI-Tregs. Here we demarcate three interconnected nodes (transcription factors, surface receptors, constitutive intracellular signals) that together program Treg immunosuppression. Reprogramming of TI-Tregs from immunosuppressive to immune stimulatory activities is achieved by the disruption of these critical pathways. TI-Tregs, Tumor-infiltrating regulatory T cells

Fig. 4 Functions of TF; MALTi induces Treg reprogramming; adjustment functions of Tfr; targeted protein degradation. (A) TFs bind DNA in a sequence-specific manner and regulate transcription. In addition, TF activity can be regulated by other signalling pathways or in interaction with other proteins to fine-tune gene expression. (B) Notion of MALT1 inhibitor arouses Treg reprogramming in TIME. Activated Tregs that inhabit CTLs are reprogrammed by MALT1 inhibitors (MALTi) into IFNγ-expression Tregs. Synthesized IFN-γ in an attempt to enhance local immune inflammation. Reprogrammed Tregs both enhance the recruitment and function of CTLs but also overexpress PD-L1 on cancer cells, causing acquired resistance. (C) Tfr cells suppresse Tfh cells and B cells through direct interaction and cytokine release. Tfr cells release TGF-β and IL-10, which inhibit the activation of Tfh cells. Additionally, Tfr cells possesse the ability to suppress Tfh cells secretion of IL-21. Moreover, the Tfr cells-expressed IL-1R2 and IL-1Ra receptors compete with the Tfh cells-surface IL-1R1 receptor for IL-1 binding. Tfr cells could build a tighter immunological synapse with B cells by producing the receptors PD-1 and CTLA4, and they could also undermine B cell activation through releasing TGF-β. Likewise, IL-10 increases B-cell activation. (D) A small molecule recruits the E3 ubiquitin ligase substrate receptor CRBN to Helios, thereby promoting its degradation. Disruption of Helios results in the destabilization of Tregs. TF, Transcription factors; CTLs, cytotoxic T cells; MALT1, Mucosa-associated lymphoid tissue protein 1; TIME, tumor immune microenvironment; Tfr, follicular regulatory T; Tfh, T follicular helper

A multitude of studies have shown that genetic or pharmacological modulation of several transcription factors, like Eos, enhancer of zeste homolog 2 (Ezh2), and Helios, resulted in Treg reprogramming [41–43]. Meanwhile, compared with Tregs in secondary lymphoid organs and normal nonlymphoid tissues, TI-Tregs display a different transcriptional program, illustrating the viability of precisely disrupting the TI-Treg transcriptome for enhancing anti-tumor immunity [44].

Forkhead box protein P3 (Foxp3)

Foxp3 could trigger nTreg production in thymus and is essential for the differentiation and suppressive function in periphery. Thus, Foxp3 is regarded as the primary regulator of Treg lineage commitment [45]. Research manifested that conventional CD4+ T cells ectopically expressing Foxp3 would gain the same phenotype and function as Tregs [46, 47]. Foxp3 is crucial for the functional stability of Tregs [48–50]. Lahl et al. performed that the deletion of Foxp3 in scurfy Tregs abrogated individual suppressive activity, which led to a rare autoimmune disorder in humans and provoked effective anti-tumor immunity [51]. Meanwhile, Tregs with elimination of Foxp3 by a certain extent of stimulation were reprogrammed into various effector T cell lineages that secreted proinflammatory cytokines and displayed functional plasticity both in vitro and in vivo [41, 52].

Conserved non-coding sequence 2 (CNS2) elements are intronic cis-regulatory elements in the Foxp3 locus and composed of Treg-specific demethylation regions which loci are stably unmethylated in TI-Tregs and are vital to maintaining a stable phenotype of Tregs [53, 54]. Thus, expression of Foxp3 could be specifically regulated through epigenetic alterations, especially DNA methylation, in some of these conserved non-coding sequences (CNSs) [55]. Subsequently, some research revealed that the absence of ten-eleven translocation (TET) proteins mediating the oxidation of 5-methylcytosine to achieve DNA demethylation in CNSs wasn’t sufficient to maintain Foxp3 expression and impaired peripheral Tregs [56]. Instead, TET2 deficiency in anti-tumor effector T cells increased their potential to persist as memory cells and more effectively control cancer. Targeting TETs, therefore, presents an appealing option to judiciously stop immune suppression in TIME [57].

Foxp3 and Treg lineage stability are also impacted by the histone acetyltransferase. It has been hypothesized that lentivirus-mediated knockdown of Ep300 downregulated Foxp3 expression due to the erosion of systemic Ep300-dependent acetylation, which was partly participated by CBP/Ep300 bromodomains [58]. Utilization of inhibition by Ep300 is sufficient to reduce Foxp3 and decrease the function and homeostasis of Tregs, thereby increasing anti-tumor immunity. P300i therapy is solely applied to TI-Tregs and has no role in other immune cells, so the strategy doesn’t provoke fatal auto­immunity [21], and Ep300 could be regarded as an efficient and specific target. Moreover, there are still plenty of other factors involved in the regulation of Foxp3, such as TGF-β receptor I signaling, SMAD4, and IL-6 which upregulate Foxp3 expression. And IL-6 together with IL-1 could induce genetic reprogramming in Foxp3+ Tregs52. However, Treg lineage stability doesn’t solely depend on Foxp3 expression, as Foxp3 only triggers a part of the Treg gene signature [59].

B lymphocyte-induced maturation protein 1 (Blimp1)

eTregs, a specific subset of Tregs, could be distinguished from cTregs based on the differentiation in phenotype and function and are enriched in the tumors. Blimp1 encoded by Prdm1 as another essential TI-Treg regulator specifically expresses in eTregs and identifies the TI-Treg subpopulation [60]. Ablation of Blimp1 in TI-Tregs alters their lineage into effector T cells. In TI-Tregs from Prdm1fl/flFoxp3YFP−Cre mice, the production of IL-10 and IL-35, critical negative cytokines, was declined. This resulted in the activation of TI-CD8 + T cells at the expense of Treg suppressive activity erosion. Besides the expression of IFNγ, tumor necrosis factor (TNF)-α and granzyme B was elevated, exhibiting that tumor-infiltrating Blimp1-deficient Tregs were reprogrammed [61].

The frequency of follicular regulatory T (Tfr) cells, a type of eTregs, is significantly higher and correlates with negative prognosis in numerous tumors. Meanwhile, higher tumoral Tfr cell signatures put melanoma at increased risk of metastasis [61, 62]. Tfr cells modulated by Blimp1 hinder germinal center response via suppressing T follicular helper (Tfh) cells and B cells and thus boost tumor growth (Fig. 4C). Blimp1-deficient Tfr cells exhibit impaired inhibitory activity and reduced production of Foxp3, CTLA-4, and other cytokines, contributing to inhibit interactions with Tfh cells and B cells and promote anti-tumor immunity, and these destabilized Tfr cells convert to Tfh-like cells [62, 63].

The regulatory details of Blimp1-induced modulation of TI-Treg stability depend on eomesodermin or directly impacting Foxp3. Through mediating Dnmt3a expression, restraining the IL-23R-STAT3 (signal transducers and activators of transduction-3) axis, or activating the CD25-STAT5 pathway, Blimp1 affects Foxp3. [64–66]. Deletion of Blimp1 contributes to the reprogramming of TI-Tregs and Tfr cells, causing them to remodel TIME, which is characterized by increased anti-tumor effector cells and enhanced anti-tumor effects [62]. The function of Blimp1 is selectively targeting tumoral Tregs since they have higher production of Blimp1 compared to Tregs in peripheral, and there are no appreciable changes in the frequencies and phenotype in splenic Tregs from Prdm1fl/flFoxp3YFP−Cre mice. Therefore, targeting Blimp1+ Tregs could produce powerful anti-tumor effects while limiting systemic toxicity, indicating a valuable target [61].

SREBP cleavage-activation protein (SCAP)/ sterol regulatory element-binding proteins (SREBPs)

SREBPs, which are transcription factors bound to the endoplasmic reticulum, interact with SCAP. SCAP, a protein that binds to the cell membrane, forms a complex with insulin-induced gene proteins, resulting in the inhibition of SREBP activity within the endoplasmic reticulum [67, 68]. Upon separation from insulin-induced gene proteins, SCAP/SREBPs are transported to the Golgi apparatus, where they undergo cleavage to release their transcriptionally active NH2-terminal domains. The activated NH2-terminal domains of SREBPs then enter the nucleus to initiate the transcription of target genes [69, 70].

Important functions of SREBPs have been extensively noticed, that promote lipid synthesis and uptake leading to lipid metabolism reprogramming, thereby influencing oncogenic signaling and accelerating tumor growth in malignancies [70–72]. Nevertheless, recent studies have found that SCAP/SREBP signaling is also necessary for retaining the stability and suppressive activity of Tregs in TIME. It has been reported that SREBP activity was upregulated in TI-Tregs. When SCAP was ablation, SREBPs presented inactivity and intratumoral Tregs became fragile characterized by acquisition of Foxp3 expression but abnormal IFNγ production. These demonstrated the functional state of intratumoral Tregs was SREBPs-dependent. They also found that the frequency of IFNγ+ Tregs was improved in the tumors of Foxp3CreScapfl/fl mice compared to controls and the TIME was reshaped. There were increased CD8+ and CD4+ effector/memory T cells along with TNFα produced by conventional CD8+ and CD4+ T cells and a reduced frequency of Tregs in the remodeled TIME [73].

Specifically, SCAP/SREBPs signaling coordinates the functional integrity of Tregs through retention of lipid synthesis and inhibitory receptor signaling like PD-1 in these cells. SREBP-dependent de novo fatty-acid biosynthesis acts to functional maturation of Tregs. Furthermore, PD-1 function is demonstrated as a nexus with the expression of IFNγ and Phosphoinositide 3-Kinase (PI3K) signaling which impairs the functional state of Tregs, including in TIME [73, 74]. Although SREBPs are expressed in most tissues of mammals, their activity isn’t related to supporting the function of Tregs in sustaining self-tolerance at homeostasis [75]. Thus, SCAP-deficient Tregs serve as a novel therapeutic tactic provoking effective anti-tumor immunity without discernible autoimmune.

Helios, Eos, Nuclear receptor subfamily 4, group A (Nr4a), enhancer of zeste homolog 2 (Ezh2)

Helios (IKAROS Family Zinc Finger 2, IKZF2), the zinc finger transcription factor, which is co-expressed in Foxp3+Tregs, is critical for the maintenance of Treg lineage stability and suppressive activity in TIME [76], whereas Helios-deficient Tregs diminish lineage stability and acquire effector T cell function [43, 77]. The genetic basis of this Treg reprogramming is alterations in gene expression, upregulating genes as a nexus with T helper cell differentiation and effector T cell activation [43]. This phenotypic instability is primarily established in TI-Tregs but not systemic Tregs. These unstable Helios-deficient Tregs produce pro-inflammatory cytokines and enhance immune responses against cancer, providing us with an attractive tactic for inhibiting cancer progression [78]. As an intracellular transcription factor, Helios is difficult to separate from viable cell subsets for functional research and hard to drug, whereas recently it was reported that a small molecule could recruit the E3 ubiquitin ligase substrate receptor Cereblon to Helios, thereby promoting its degradation (Fig. 4D). The small molecule degraded Helios to induce an altered-Treg phenotype consistent with previously reported Ikzf2−/− Tregs4.

Eos, also a member of the Ikaros family, in concert with Foxp3, forms a molecular complex as a paramount mediator of gene silencing arising from chromatin modifications in Tregs and thus participates in the maintenance of Treg lineage identity [79, 80]. In Tregs, silencing of Eos reprograms them to acquire immunostimulatory properties via increasing the expression of CD40L, and heightens immune responses against cancer. Frustratingly, there was research showing that mice with Tregs deficient in Eos exhibited side effects of organ-specific or systemic autoimmunity, which warrants vigilance [41, 80].

Nr4a factors are required to control Foxp3 and other Treg-associated genes to maintain Treg capacity of immunosuppression in TIME. Knockdown of the NR4A genes in intratumor Tregs attenuates Treg activity with the decrease of Foxp3 and CTLA-4 and develops effective T helper cell (Th) 1 and CTLs-associated anti-tumor immunity [81]. Nevertheless, it was hypothesized that these NR4A factors had resembled effects on intratumor Tregs and lymphoid Tregs, making it challenging to specifically inhibit intratumor Tregs, often endowing unintended side effects on lymphoid Tregs, but recently cyclooxygenase-2/prostaglandin E2 was identified as an attractive target due to this axis idiosyncratic enhancement of NR4A expression only in specific tumor tissues [82].

Ezh2 is preferentially expressed in TI-Tregs, where EZH2 is activated in a CD28-dependent manner and associates with Foxp3 trimethylates lysine 27 on histone H3 (H3K27me3) secondary to deposit H3K27me3 in regions of the genome that are supposed to remain silent, thereby suppressing inflammatory transcriptional programs [83]. The absence of EZH2 in Tregs drives phenotypic and functional alterations resulting in the acquisition of immunostimulatory functions with decreased production of immunosuppressive IL-10 and increased production of TNFα, IFNγ, and IL-2 that eliminate tumors and remodel the TIME, further supporting the role of EZH2 in Treg reprogramming [42]. In addition, EZH2 also promotes the transition of TAMs to the M2 phenotype and inhibits the Th1-type chemokine C-X-C Motif Chemokine Ligand 9 (CXCL9) to reduce CD8+ T cell infiltration, thereby reducing the anti-tumor immune response. It can also enhance the function of effector T cells and enhance the immune response through the activation of DCs. Therefore, the regulation of EZH2 to promote tumor immunity is multi-mechanism and multi-pathway [84–87].

Regulation of surface receptors in the TI-Tregs

Compared to peripheral Tregs, several surface receptors including CTLA-4, glucocorticoid-induced tumor necrosis factor (TNF) receptor (GITR), and CD25 (IL-2 receptor α-chain) which are paramount for Tregs development, stable suppression, and cytotoxicity are upregulated in Tregs in TIME [88–90]. Blocking these key receptors on Tregs has been demonstrated to attenuate the immunosuppressive activity of intratumor Tregs and replace them with pro-inflammatory activity that enhances immune responses against cancer [42, 91]. Therefore, the identification of surface receptors involved in the reprogramming of Tregs is a promising target for cancer immunotherapy.

Cluster of differentiations (CDs)

CD25 is connected with the maintenance of high Foxp3 expression and lineage identity of Foxp3+ Tregs. Upon activation, CD25 phosphorylates and activates STAT5 which directly binds to the CNS2 intronic element, thereby affecting the expression of Foxp3, and programming immunosuppressive Tregs [78, 92]. Rech and colleagues treated human Tregs in vitro with the CD25-blocking monoclonal antibody, daclizumab, leading to selective downregulation of Foxp3, loss of inhibitory function of the Tregs, and re-secretion of IFNγ, consistent with reprogramming. In vivo, daclizumab mitigated Tregs in patients with metastatic breast cancer as expected and boosted robust CD8+ and CD4+ T cells in the absence of autoimmunity. They have validated that CD25-blocking could reprogram Tregs and promote T cell cancer immunosurveillance while avoiding autoimmunity. It should be noted, however, that most CD25 monoclonal antibodies pose an autoimmune risk in addition to daclizumab [91].

CD28 co-stimulation, an extracellular cue as the most potent secondary stimulus, plays critical roles in Tregs maintenance via multiple pathways, including induction of Foxp3, and regulation of the chromatin-modifying enzyme like EZH2. Noteworthy, activation of LCK (lymphocyte cell-specific protein tyrosine kinase) seems to be especially significant for Tregs. LCK is engaged in the induction and nuclear localization of nuclear factor kappa-B (NF-κB) to retain the functional integrity of Tregs in cancer [83, 93, 94]. The PI3K-AKT (protein kinase, strain AK, Thymoma)-mTOR (mammalian target of rapamycin) pathway decreases AKT activation in response to CD28 in Tregs, which hasn’t been demonstrated for its role in Treg survival and maintenance of inhibitory activity. Blocking CD28 signalling in Tregs impairs their stability and function, inhibits their ability to suppress anti-tumor immune responses, and facilitates tumor surveillance [95].

TNF receptor (TNFR) superfamily member CD357, namely GITR, is substantially increased during T-cell activation and is constitutively expressed in Tregs. GITR pathway activation abrogates tumor immune suppression through loss of Treg lineage stability [96]. Anti-GITR agonistic antibody therapy reprograms Tregs into anti-tumor Th1-like CD4+ T cells with the expression of IFNγ and the acquisition of cytotoxic activity against tumor cells and converts the immunosuppressive TIME into an immunostimulatory milieu causing tumor regression [37]. Mechanistically, anti-GITR causes alteration of diverse transcription factors and cytokines, for instance, downregulation of Foxp3, Helios, and IL-10 and upregulation of Eomes and IFNγ in TI-Tregs [96]. IFNγ produced by transformed Tregs may also have the additional role of driving the reprogramming of subsequent intratumor Tregs, as has been demonstrated in observations of Helios−/−, NRP1−/−, and/or CARMA−/− Tregs. It has been manifested that IFNγ produced by NRP1−/− Tregs is capable of reprogramming wild-type [37]. Further, mice with genetic ablation of GITR in Tregs are shown to specifically affect intratumor Tregs without peripheral autoimmunity reported [97].

Neuropilin-1 (Nrp-1)

Nrp1, a transmembrane glycoprotein, is expressed by ~ 90% of TI-Tregs in mouse models of cancer and acts as a co-receptor for vascular endothelial growth factors (VEGFs) isoforms mediating cell migration. Removal of Nrp-1 expression in Tregs prevents their recruitment to the tumor locus, thereby delaying the growth and progression of tumors, which could be reinstated by transferring Nrp-1+ Tregs adoptively from WT mice [74, 98]. Nrp1 deficiency destabilizes surrounding wild-type Tregs and loses their inhibitory activity yet retains expression of Foxp3, which is the Treg ‘fragility’. More strikingly, when they enter TIME, they are reprogrammed into IFNγ-producing cells promoting tumor clearance without autoimmune abnormalities [74]. Specifically, Nrp-1 recruits PTEN (phosphatase and tensin homolog deleted on chromosome ten) to disrupt pAKT (phosphorylated protein kinase, strain AK, Thymoma), forms the semaphorin 4 A-neuropilin 1 axis and participates in the interaction of Tregs with immature DCs, thus strengthening TI-Treg function and limiting anti-tumor immunity, while it is dispensable for Tregs to maintain immune homeostasis [74, 98–100].

Folate receptor delta (FRδ)

FRδ has been exploited as a biological marker for Tregs due to its exclusive expression on Tregs and oocytes [101, 102]. It has been recently discovered that the FRδ-Izumo relationship promotes immune synapses to form between Tregs and γδT cells [103]. Simultaneously, a high-affinity folate analogue, raltitrexed, has been identified to specifically bind to FRδ in tumors other than peripheral blood and healthy tissues. This specific ligand has been used to selectively target therapeutic agents (imaging agents, immune activators, and immunosuppressants) to Tregs in murine tumor xenografts. For instance, delivery of a TLR7 agonist to Tregs has been shown to reprogram the TIME into a state of lower immune suppression, resulting in approximately 40–80% reduction in tumor development without causing appreciable systemic damage [104].

PD-1

Research has shown that the expression of PD-1 on Tregs promotes the homeostasis and functionality of Tregs. In mice with conditional deletion of PD-1, the function of TI-Tregs declines, and their numbers are reduced. Meanwhile, Foxp3 tracking experiments indicate that the expression of PD-1 is crucial for the stability of Foxp3 expression in TI-Tregs, as Foxp3 expression is downregulated. Single-cell analyses reveal that PD-1 signalling enhances lipid metabolism, proliferation, and inhibitory pathways in TI-Tregs. Foxp3 has been reported to regulate the suppressive function of Tregs by suppressing glycolysis and enhancing oxidative phosphorylation. These findings suggest that the absence or inhibition of PD-1 can weaken the lineage stability and metabolic adaptability of Tregs in TIME by reducing Foxp3 expression, thereby enhancing anti-tumor immunity [105–107]. However, the function of PD-1 in TI-Tregs remains controversial. In EAE mice, the expression of PD-1 has been reported to inhibit the immunosuppressive function of Tregs. Furthermore, a higher incidence of progressive disease has been observed in some cancer patients receiving anti-PD-1 treatment [108, 109]. Another study reported that excessive progression was unrelated to the activity of TI-Tregs but was associated with the pre-treatment frequency of CD39+ CD8+ T cells [110]. Thus, further research is necessary to understand how PD-1 functions in Tregs depending on the situation.

CTLA-4

CTLA-4 is a homolog of CD28 and is constitutively expressed on the surface of Tregs. CTLA-4 competes with CD28 for binding to CD80/CD86 on antigen-presenting cells (APCs), thereby inhibiting CD28-mediated co-stimulation of T cells [88, 111]. According to certain research, CTLA-4 can reduce the immunosuppressive activity of Tregs. Immune checkpoint blockade with anti-CTLA-4 significantly increases the expression of EZH2 in the TIME and may enhance the suppressive activity of TI-Tregs [42]. Anti-CTLA-4 monoclonal antibodies can also deplete Tregs, and in cancer patients, there is a strong correlation between the clinical efficacy of Ipilimumab and the reduction of Treg numbers in tumor tissues [28]. The effects of CTLA-4 blockade on Tregs are complex, and different antibodies may have distinct mechanisms of action (for instance, either depleting Tregs or functionally inhibiting them without depletion) [112, 113]. Therefore, while CTLA-4 is an attractive target for destabilizing and reprogramming Tregs, its effects still require further investigation.

T cell immunoglobulin and ITIM domain (TIGIT)

TIGIT is an inhibitory receptor expressed on lymphocytes, primarily on activated T cells, NK cells, and Tregs. It has recently emerged as a major new target in cancer immunotherapy [114]. TIGIT competes with CD226 for interaction with CD112 and CD155 (PVR). The CD155/TIGIT signaling pathway exerts immunosuppressive effects by exacerbating cellular exhaustion, leading to tumor immune evasion. TIGIT signalling has the potential to enhance the suppressive function of Tregs [115]. Agonistic monoclonal antibodies to human TIGIT (hu-TIGIT) have been reported to induce Treg effector molecule fibrinogen-like protein 2. These antibodies are an agonistic monoclonal antibody targeting TIGIT that selectively and potently suppresses T follicular helper (Tfh) cells while promoting the suppressive function of Tregs [116]. Besides, TI-Tregs respond to Fc-active anti-TIGIT antibodies and downregulate immunosuppressive gene programs.

Conversely, other studies indicate that increased expression of TIGIT on Tregs is associated with decreased Treg function. Aspirin has shown significant anti-colorectal cancer effects in mice. During related mechanistic studies, it was found that there were more CD155 tumor cells and CD4+ CD25+ Tregs, with increased TIGIT levels following aspirin treatment. The high expression of TIGIT reduces the functionality of Tregs, thereby decreasing their immunosuppressive effects and promoting the anti-tumor actions of other immune cells in the colorectal cancer (CRC) immunological microenvironment [117].

Chemokine receptors

After activation, Tregs specific express the accompanying chemokine receptors, such as the chemokine receptors C-C Motif Chemokine Receptor (CCR) 4 and CCR8. Focusing on specific subsets of TI-Tregs by evaluating their chemokine receptor expression is currently a key area of research for cancer treatment [118].

CCR4 and CCR8 have recently been identified as being more selectively expressed on tumor-reactive eTregs [90, 119, 120]. The expression of CCR4 demonstrates an enhanced ability to suppress effector T cells. Functionally, CCR4+ Tregs are more immunosuppressive compared to CCR4− Tregs. Pharmacological antagonism of CCR4 resulted in a decreased frequency of Tregs and hindered the maintenance of the TI-Treg pool [121].Moreover, antagonizing CCR4 prevented the accumulation of macrophages and myeloid-derived suppressor cells (MDSCs), which are two other suppressive cell types that contribute to immune evasion. This positions CCR4 antagonism as a potentially more versatile strategy for anti-tumor immunotherapy [122, 123].

Besides, CCR4 ligands are found to be upregulated in tumors following treatment with checkpoint inhibitors. The blockade of CCR4 demonstrated a synergistic anti-tumor effect in conjunction with these immunomodulatory agents [121].

The results of a single-cell analysis of TI-Treg revealed that multiclonal Tregs predominantly express the chemokine receptor CCR8, which correlates with enhanced activation and suppressive capabilities. Compared to CCR8–TI-Tregs, CCR8+TI-Tregs exhibit enhanced activation, greater suppressive characteristics, and increased stability, as demonstrated by elevated expression of activation and suppression markers and Treg-specific DNA hypomethylation. Targeting CCR8 with anti-CCR8 mAb not only reduced multiclonal Tregs specifically in tumor tissues but also evoked strong anti-tumor immune responses without causing harmful autoimmunity [34, 90, 120, 124]. Ultimately, CXCR3 serves as the key chemokine receptor for Th1 cells, while CCR6 is characteristic of Th17-like Tregs. Targeting these receptors may similarly achieve tumor-modulating effects, although this warrants further investigation [125, 126].

Regulation of other constitutive intracellular signals in the TI-Tregs

In addition to cell surface-specific receptors and intracellular transcription factors, there are miscellaneous other intracellular signals involved in the regulation of Treg reprogramming.

CARMA1-BCL10-MALT1 (CBM) signalosome complex

CBM is ubiquitously and heterogeneously expressed in almost all human tissues and cells and is an essential mediator of immune signaling. In lymphocytes, CBM signalosome assembled by CARD11 (caspase recruitment domain 11, also known as CARMA1), BCL10 (B cell lymphoma/leukemia protein10) and MALT1 (Mucosa-­associated lymphoid tissue protein 1, also termed paracaspase 1), mediates the activation of NF-κB and Jun N-­terminal kinase (JNK) on ligand binding to T/B cell receptor signalling. This alters relevant cellular activation, differentiation, and effector function [127, 128]. CBM is necessary for nTreg development, iTreg induction, and the conversion of cTregs to eTregs under steady-state conditions, as well as crucial for accessing the capacity of suppression of Tregs [127, 129]. Constitutive genetic disruptions in its any component could hurdle thymic Treg development, abrogate inhibitory function of mature Tregs, and a majority of TI-Tregs produce IFNγ, rising to decelerate tumor growth [24, 127].

In inflammatory conditions, Treg-specific ablation of the scaffold protein CARD11, destabilizes Tregs in tumor tissues and secretes IFNγ to decline tumor growth, revealing its primary role in the depression of anti-tumor effects. In this condition, only eTregs express Th1 lineage-defining transcription factor undergoing a lineage identity transition, and these shift Tregs maintain Foxp3 expression [24]. Whereas in the context of non-inflammatory lack of CARD11 doesn’t cause the above-mentioned change. The regulatory mechanisms of CARD11 deficiency include not only the failure of NF-κB signaling [130]. but also reduced expression and TCR-induced phosphorylation of the JUN. Additionally, there are alterations in the phosphorylation of Forkhead box O1 (Foxo1) [131]. Notably, selective ablation of both alleles of CARD11 in Tregs endowed fatal immune pathology, while partial deletion of CARD11 in only a fraction of Tregs to provoke their production of the IFNγ and TNF was sufficient to generate anti-tumor effects and avoid detectable immune pathology. Heterozygous CARD11-damaged mice were healthy and had a normal lifespan, but transplant cancers grew more slowly in these animals. Interestingly, tumor cells raised PD-L1 production, which widely validated activation of adaptive immune resistance. Consequently, tumors ineffective on anti-PD-1 monotherapy were rejected when PD-1 inhibition and CARD11 deletion were combined [24].

Activated CARD11 interacts with BCL10 and promotes BCL10 formation of macromolecular filaments, providing a large scaffold for MALT1 binding and activation. The formation of BCL10 filaments is also essential for amplifying BCR/TCR signalling and the robust activation of downstream NF-κB [132]. Studies in BCL10 conditional knockout mice have demonstrated that deletion of BCL10 in immature Tregs decreases Treg populations, whereas specific deletion of BCL10 in mature Tregs impairs the inhibitory function of mature Tregs, leading to their transformation into IFNγ-producing pro-inflammatory cells with much higher expression of transcription factor T-bet and hypoxia-inducible factor-1α (HIF-1α) [15].

Similar anti-tumor activity is also observed following ablation of MALT1 in Tregs which is the molecular scaffolding and enzymatic paracaspase domain of the CBM complex that further activates the downstream functions of diverse effector molecules [132]. Counterintuitively, neither TNF receptor-associated factor 6 (TRAF6) deficiency nor destruction of MALT1-TRAF6 interaction influences NF-κB activation in response to inflammatory TNFα, revealing MALT1 protease activation primarily drives NF-κB signalling which controls the development and suppressive functions of Tregs [133]. MALT1 protease activity is required for Tregs to be susceptible to innate immunological stimulation and maintains high CTLA-4 levels on Tregs, thus MALT1 has a pivotal function in balancing thymic and peripheral tolerance. MALT1 paracaspase dysregulation selectively reprograms immunosuppressive Tregs to a pro-inflammatory fragile state in TIME and gives rise to ‘scurfy-like’ autoimmune syndromes [134] (Fig. 4B). Therefore, when reprogramming TI-Tregs with MALT1 inhibitors for the treatment of solid tumors, attention for occurrence of autoimmune toxicity is warrant [135].

Noncoding RNAs

Tregs are also regulated by abnormal molecular expression of noncoding RNAs, including microRNAs (miRNAs/miRs) and long noncoding RNAs (lncRNAs), which don’t translate proteins but instead interact with transcription factors defining Treg function and improving anti-tumor responses [136–138]. MiRNAs interact with multiple transcription factors. Firstly, they interact extensively with Foxp3. MiRNA profiles could reinforce Foxp3 expression maintaining Treg suppressive capacity. Impairment of miRNA function downregulates the level of microRNA-mediated Foxp3 and develops fatal systemic autoimmune disease. Furthermore, miRNAs are also direct or indirect targets of Foxp3 which conjugates vicinity of miRNA-encoding intergenic sequences in Tregs. In addition, miRNAs such as miR-155 cooperate with Foxp3 to coordinate the regulation of other key genes in Tregs, including special AT-rich sequence binding protein 1 (SATB1) and Zinc finger E-box binding homeobox 2 (ZEB2) [139–141]. This interaction could be observed in investigations of miR-31. Secondly, miRNAs mediate the transcription factor Foxo1, which binds directly to the Foxp3 motif to support Foxp3 expression and also acts on the Ifng motif to repress Ifng expression [142, 143], playing a vital role in early Treg lineage stability. For example, miR-92a abrogates Treg homeostasis and function and facilitates Tregs acquiring an inflammatory phenotype by repressing Foxo1. Research has shown that exposure of wild-type Tregs to inflammatory environments results in an increase in IL-17 A or IFN-γ. In contrast, miR-92a−/− Tregs continue relatively resistant to these inflammatory cytokine-mediated changes both in vivo and in vitro. In the meantime, these inflammatory stimuli have caused upregulation of miR-92a correlated with decreased expression of the miR-92a target Foxo1 in WT Tregs. These results suggest that miR-92a targeting Foxo1 boosts the procurement of inflammatory Treg phenotype and destroys Treg suppressive function [136].

Afterward, there are also other sorts of miRNAs involved in the regulation of Tregs. For example, miR-101 and miR-26a regulate EZH2, which is relevant for Foxp3 to retain suppressive capacity of nTreg in mice. miR-155 significantly decreases the abundance of Tregs [144–146]. Foxp3CremiR-142fl/fl mice negatively regulate the frequencies and suppressor function of Tregs [147]. Loss of miR-181a/b-1 increases Treg inhibition function and negatively associates with the expression of CTLA-4 protein in the thymus and peripheral Tregs. Similarly, the miR-17-92-deficient Tregs lead to tumor immune evasion [148, 149]. Distinct miRNA profiles of human nTregs include miRNAs that positively regulate the expression of key Treg genes, such as miR-21 [150], 125a, 142 [151], 146a, 181c, and 374 [152], as well as negative regulator miRNAs, such as miR31 miR-155 miR-181a/b-1[153, 154]. These miRNAs comprise part of a network of regulatory factors in Tregs (Table 1) [153, 154].

Table 1 Noncoding RNAs influence the stability of Tregs

Noncoding RNAs	Function	References	
MiR31	1. Target the 3’ UTR of Foxp3 mRNA to negatively regulate Foxp3 expression.

2. Discover a target sequence for Foxp3 within the mouse miR-31 encoding gene’s promoter region, indicating that Foxp3 may directly target miR-31.

	[150, 196, 197]	
MiR92a	1. Abrogate Treg homeostasis and function and facilitate Tregs acquiring an inflammatory phenotype by repressing Foxo1.	[136]	
MiR-101 and MiR-26a	1. Regulate EZH2 to stabilize Foxp3.	[144]	
MiR-155	1. Decrease the abundance of Tregs.

2. Cooperate with Foxp3 to regulate special AT-rich sequence binding protein 1 (SATB1) and Zinc finger E-box binding homeobox 2 (ZEB2).

	[144]	
MiR-142	1. Impact the frequencies and suppressor function of Tregs	[147]	

LncRNAs are untranslated transcripts longer than 200 bp that are subtle regulators of gene expression through interaction with mRNAs and chromatin [155, 156]. The important role of lncRNA in Treg commitment has been proven dependent on binding to Foxp3 conserved noncoding elements and influencing its expression. Silencing lncRNA leads to the downregulation of Foxp3. This could be a necessary condition for Treg transcriptional reprogramming in response to external stimuli like decreased IL-2 signaling, supporting the fact that transcriptional networks could undergo very little alterations to generate plasticity [157, 158].

IL-33

Intranuclear IL-33 affects Tregs’ transcriptional profile and determines their activity in the anti-tumor immune response. IL-33-deficient Tregs exhibit compromised suppressive capabilities and aid in the elimination of tumors as well as the development of strong anti-tumor immunity. Ablation of IL-33 reprograms Tregs to upregulate IFNγ expression and maintain Foxp3 expression, consistent with a “fragile” phenotype, which exhibits reduced suppressive function in vivo, thereby accelerating tumor regression [159, 160]. The molecular events that elevate IFNγ production depend on the NF-κB-T-bet–IFNγ axis in IL-33-deficient Tregs. Gene enrichment analysis showed that Tbx21 which codes for T-bet and is an essential hub in the Ifng gene regulation network was differentially expressed in IL-33−/−Tregs comparison with control. In support, TI-Tregs from Foxp3CreIL33fl/fl mice displayed significantly more T-bet expression than control Foxp3Cre mice and increased accessibility of the site of T-bet binding in the regulatory region of the Ifng locus. What’s more, the expression of T-bet is regulated by intracellular IL-33-regulated NF-κB signaling which inhibition significantly downregulates T-bet and IFNγ expression. Combinedly, these findings claim that in IL-33−/− mice TI-Treg reprogramming is in an NF-κB-T-bet-IFNγ manner [161, 162].

Alterations in extracellular targets in TIME induce TI-Treg reprogramming

Regulation of inflammatory factors drives Treg reprogramming in TIME

At sites of inflammation, Tregs become dysfunctional and undergo rapid reprogramming into Th1 or Th17 expressing inflammatory cytokines [136]. Both in vitro and in vivo, exposure to IL-6 changes the fate of Tregs transdifferentiate into Th17 expressing Th17-specific genes and downregulation of Foxp3 [163]. In anti-tumor immunotherapy, blocking the IL-6 receptor (IL-6R) on Tregs results in the loss of the ability to destabilize and reprogram Tregs [164, 165]. Early in vitro studies found Foxp3 expression was decreased in activated Tregs with the presence of IL-6, which is mediated by STAT3, RAR-related orphan nuclear receptor (ROR) α, and RORγt [163, 166]. IL-6 facilitates STAT3, a critical component of signal transduction, inducing a series of miRNAs that cause IL-17-producing, diminishing Foxp3 expression, and causing RORγt to dissociate from Foxp3. Secretion of IL-17 and IL-17 F is dependent on RORα and RORγt. Subsequently, the generation of IL-17-secreting Tregs and Th17 is induced [52, 163]. It is of note that IL-6 appears to also drive Eos downregulation, which has been proven to be an important driver of Treg reprogramming. Moreover, the addition of high concentrations of neutralizing anti-IL-6 to the co-cultures overcomes the lack of Eos and prevents functional reprogramming [163].

IFNγ is also critical for Treg dysfunction. Its ablation restores IL33−/−Treg suppressive properties and IFNγ produced by transformed Tregs, as mentioned above, may also have an additional role of driving subsequent intratumoral Treg reprogramming. The instability of Tregs was discovered to require the expression of the IFNγ receptor (IFNγR1), indicating the possibility of an IFNγ-driven autocrine or paracrine loop [37]. Notably, deletion of IFNγR renders Tregs unresponsive to this destabilizing IFNγ, and then traditional PD-1 checkpoint blockade immunotherapy fails [74]. Thus, pro-inflammatory cytokines appear to convey important signals that disrupt the stability of tumor-associated Tregs. And, among the massive models tested, this successful immunotherapy requires an unstable effect on Tregs.

DCs involve in TI-Treg reprogramming

Proverbially, TIME contains a variety of immune cells with a wide range of interactions that are capable of recruitment, inducement, and maintenance of Tregs. Inflammatory DCs are required for Treg reprogramming, driving a substantial fraction loss of suppressor phenotype and acquisition of pro-inflammatory phenotype. Sharma and colleagues used a co-culture model in vitro to validate that reprogramming required activated DCs rather than resting DCs to trigger IL-6 expression and cognate interaction with Tregs via MHC II [163]. Besides, tolerogenic tumor-associated DCs express IDO (indoleamine 2,3 dioxygenase), PD-L1, or semaphorin-4a (the ligand for Nrp1) to resist the inflammation-induced reprogramming of Tregs in vivo. Mechanisms by which IDO affects Treg reprogramming include blocking IL-6 production through effects on NF-IL6 (CEBP) or activating the General control nonderepressible 2 (GCN2) kinase pathway in Tregs phosphorylating the ribosomal translation factor eukaryotic Initiation Factor 2 (eIF2) to alter ribosomal translation of mRNA species [20] (Fig. 5). This event also occurs in tumor-draining LNs, as before, Sharma used plasmacytoid DCs (pDCs) expressing IDO from tumor-draining LNs co-cultured with Tregs in vitro to demonstrate [163]. Interestingly, IDO-expressing macrophages have been found in carcinomatous ascites, so there may be more than one type of antigen-presenting cell capable of expressing IDO in human tumors and tumor-draining LN and they may also perform a function to influence Treg reprogramming, which remains to be established [20].

Fig. 5 Effects of inflammatory factors and DCs on Treg stability. Two key pro-inflammatory cytokines, IL6 and IFNγ, deliver important signals that destabilize TI-Tregs. Inflammatory DCs participate in the reprogramming of Tregs through triggering IL-6 expression and cognating interaction with Tregs via MHC II. Tolerogenic tumor-associated DCs express IDO, PD-L1, or semaphorin-4a (the ligand for Nrp1) as well as restrain IL-6 expression and interaction with Tregs to resist the inflammation-induced reprogramming of Tregs in vivo. TI-Tregs, Tumor-infiltrating regulatory T cells; DCs, Dendritic cells; IDO, indoleamine 2,3 dioxygenase; Nrp1, Neuropilin-1

Translation of results: Treg reprogramming in therapy

Clinical strategies of Treg reprogramming for oncology treatment

The instability of intratumoral Treg populations alters the immune response to tumor cells, with profound therapeutic implications. A wide variety of components are involved in the Treg reprogramming process, which we have summarized here (Table 2). Based on the above understanding, one possible clinical strategy that has been proposed is to block one of the known Treg-stabilizing signals in Tregs or TIME, such as MALT1, or Helios. Pleasantly, two clinical candidates of potent and selective allosteric MALT1 inhibitors, JNJ-67,856,633 [167] and MPT-0118, have been developed based on structure-guided drug research. Clinical trials adjudicate the role of MPT-0118 as a single agent or in combination with PD-1 blockade in Treg phenotypic transformation by a tumor-cell extrinsic pathway [168]. Considering the dual effects of MALT1 in immune TIME and cancer cells, that is, inhibiting MALT1 protein activity affects tumor cell proliferation, survival, and invasion while reprogramming activates Tregs to secrete IFNγ, the use of MALT1 inhibitors could appropriately multiply the anti-tumor immunity, improve ICT response in solid cancers, and reduce tumor cell growth and infiltration with less effort. It has reported the discovery of NVP-DKY709, a selective molecular glue degrader of IKZF2(Helios) that preserves IKZF1/3. Treatment with NVP-DKY709 reduced the inhibitory activity of human Tregs and rescued cytokine production in depleted T effector cells. Its role of delayed tumor growth in mice with a humanized immune system and cynomolgus monkeys has been confirmed. NVP-DKY709 is being investigated in the clinic as an immune enhancer for cancer immunotherapy [169]. Meanwhile, pharmacological Helios degraders VLV1, and VLV2, novel small molecule ligands of CRBN, also disrupt phenotypic stability and reduce the inhibitory activity of human Tregs in vitro, establishing a route towards Helios-targeting therapeutics. Encouragingly, targeted protein degradation has been found in the R&D process, which is the development pathway for emerging small molecules used to induce ubiquitination and subsequent proteasomal degradation of target proteins, which have the potential to expand the druggable proteome [4].

Table 2 Representative factors to reprogram TI-Tregs.

Target	Category	Description	Mechanisims of action	References	
Foxp3	Transcription factors	1. Forkhead/winged-helix family of transcriptional regulators.

2. Trigger the production of tTregs and regulate the differentiation and inhibitory function of pTregs.

3. Trigger the transcription of Treg characteristic genes and maintain the stable phenotype of Tregs.

	-	[45, 59, 182–184]	
Blimp1	Transcription factors	1. The zinc finger protein family and repressor of beta-interferon gene expression.

2. Involved in the production of IL-10 and IL-35.

3. Regulate Tfr cells and deletion of Blimp1 facilitates the reprogramming of Tfr cells.

4. Elimination of Blimp1 in TI-Tregs changes their lineage to Teff.

	1. Depend on eomesodermin or directly impact Foxp3 through mediating Dnmt3a expression to maintain the methylation of CNS2.

2. Restrain the IL-23R-STAT3 axis.

3. Activate the CD25-STAT5 pathway.

	[61–66, 185]	
SCAP/SREBP	Transcription factors	1. In the presence of cholesterol, SCAP binds and hydrolyzes to activate SREBPs.

2. SREBPs promote lipid synthesis and uptake, leading to lipid metabolism reprogramming.

3. Maintain the stability and inhibitory activity of TI-Tregs.

4. Deletion of SCAP leads to an increase in the frequency of IFNγ + Tregs.

	1. Induce de novo fatty-acid biosynthesis to boost functional maturation of Tregs.

2. Sustain PD-1 function to maintain expression of IFNγ.

	[70–74]	
Helios	Transcription factors	1. The Ikaros family of zinc-finger proteins.

2. Unstable Helios-deficient Tregs produce pro-inflammatory cytokines and enhance immune responses against cancer.

	1. Stabilize the phenotype of Tregs, possibly via signal transducer and activator of transcription 5 (STAT5)–mediated signaling and prevention of interleukin-2 (IL-2) production in Tregs by epigenetic silencing.	[78, 186, 187]	
Eos	Transcription factors	1. The Ikaros family.

2. In concert with Foxp3, form a molecular complex to silence genes.

3. Participate in the maintenance of Treg lineage identity.

	-	[79, 80]	
Nr4a	Transcription factors	1. The steroid-thyroid hormone-retinoid receptor superfamily.

2. Promote the development of Tregs by cooperating with other Treg developmental mechanisms.

3. Exhaustion of NR4A attenuates Treg activity with the decrease of Foxp3 and CTLA-4 and develops Th1 and CTLs-associated anti-tumor immunity.

	1. Control Foxp3 and other Treg-associated genes.	[81, 188, 189]	
Ezh2	Transcription factors	1. The Polycomb-group (PcG) family.

2. The absence of EZH2 in Tregs drives the acquisition of immunostimulatory functions with decreased production of immunosuppressive IL-10 and increased production of TNFα, IFNγ, and IL-2.

	1. Be activated in a CD28-dependent manner and participate in Foxp3 trimethylates lysine 27 on histone H3 secondary to remain genome silent.	[42, 83, 184, 190–192]	
CD25	The IL-2 receptor α chain	1. Together with the common beta (IL2RB) chains and gamma chain (IL2RG), constitute the high-affinity IL2 receptor.

2. CD25-blocking leads to selective downregulation of Foxp3, loss of inhibitory function of the Tregs, and re-secretion of IFNγ.

	1. Phosphorylate and activate STAT5 which directly binds to the CNS2 intronic element, affecting the expression of Foxp3, and programming immunosuppressive Tregs.	[78, 91, 92]	
CD28	Receptors for costimulatory molecules	1. Participate in T-cell proliferation and survival, cytokine production, and T-helper type-2 development.	1. Induce Foxp3, and regulate the chromatin-modifying enzyme like EZH2.	[83, 93]	
GITR	Receptors	1. The TNF receptor (TNFR) superfamily.

2. Play a key role in dominant immunological self-tolerance maintained by CD25(+) CD4(+) Tregs.

3. Anti-GITR agonistic antibody therapy reprograms Tregs into anti-tumor Th1-like CD4 + T cells with the expression of IFNγ.

	1. Alter diverse transcription factors and cytokines, for instance, downregulation of Foxp3, Helios, and IL-10 and upregulation of Eomes and IFNγ in TI-Tregs.	[37, 96, 193]	
Nrp1	Receptors	1. The co-receptor for vascular endothelial growth factors isoforms mediating cell migration.

2. Nrp1-deficient destabilizes Tregs and contributes to Treg ‘fragility’.

3. When ‘fragility’ Tregs enter TIME, they are reprogrammed into IFNγ-producing cells promoting tumor clearance.

	1. Recruit PTEN to disrupt pAKT.

2. Form the semaphorin 4 A-neuropilin 1 axis.

3. Participate in the interaction of Tregs with immature DCs.

	[74, 98–100]	
FRδ	Receptors	1. Predict to be located in extracellular region and plasma membrane.

2. Promote immune synapses to form between Tregs and γδT cells.

	-	[104]	
PD-1	Receptors	1. An important immunosuppressive molecule.

2. The function of PD-1 in TI-Tregs remains controversial.

	1. Reduce Foxp3 expression.

2. As a nexus with the expression of IFNγ and Phosphoinositide 3-Kinase (PI3K) signaling

	[105–107]	
CTLA-4	Receptors	1. Anti-CTLA-4 enhances the suppressive activity of TI-Tregs and depletes the number of Tregs.	1. Increase the expression of EZH2.	[42, 88]	
TIGIT	Receptors	1. Expressed as an inhibitory receptor on lymphocytes.

2. Enhance the suppressive function of Tregs.

	1. Induce Treg effector molecule fibrinogen-like protein 2.	[114–116]	
CCR4	Receptors	1. CCR4+ Tregs are more immunosuppressive compared to CCR4- Tregs.

2. Prevent the accumulation of Tregs.

	-	[121, 194]	
CCR8	Receptors	1. Exhibit enhanced activation, greater suppressive characteristics, and increased stability.	-	[34, 90, 120]	
CBM signalosome complex	Immunomodulatory protein complex	1. Assembled by CARD11, BCL10 and MALT1.

2. Promote nTreg development, iTreg induction, and the conversion of cTregs to eTregs under steady-state conditions, as well as accessing the capacity of suppression of Tregs.

3. Constitutive genetic disruptions in its any components hurdle tTreg development, abrogate inhibitory function of mature Tregs, and a majority of TI-Tregs produce IFNγ.

	1. Trigger NF-kappaB signaling, Jun N-­terminal kinase and lymphoctye activation following antigen-receptor stimulation.

2. Possibly regulate Akt activity.

	[127–129]	
MiRNAs	Noncoding RNAs	1. Reinforce Foxp3 expression to maintain Treg suppressive capacity.	1. Bind the 3’-untranslated regions of target mRNAs to increase mRNA digestion or block mRNA translation and thus, involve in post-transcriptional regulation of gene expression.

2. Mediate the transcription factor Foxo1, which binds directly to the Foxp3 motif to support Foxp3 expression and also act on the Ifng motif to repress Ifng expression.

	[136]	
lncRNAs	Long noncoding RNAs	1. Silence lncRNA leading to the downregulation of Foxp3.	1. Interact with mRNAs and chromatin to regulate gene expression.	[155]	
IL-33	Pro-inflammatory cytokine	1. Affect Tregs’ transcriptional profile and determine their activity.

2. Ablation of IL-33 reprograms Tregs to upregulate IFNγ expression and maintain Foxp3 expression, consistent with a “fragile” phenotype.

	1. Depend on the NF-κB-T-bet–IFNγ axis.	[161, 195]	
IL-6	Pro-inflammatory cytokine	1. Change the fate of Tregs transdifferentiate into Th17 expressing Th17-specific genes and downregulation of Foxp3.	1. Reduction of Foxp3 is mediated by STAT3, RAR-related orphan nuclear receptor (ROR) α, and RORγt.

2. Induce a series of miRNAs causing IL-17-producing, diminishing Foxp3 expression, and causing RORγt to dissociate from Foxp3.

	[163, 166]	
IFNγ	Pro-inflammatory cytokine	1. Its ablation restores IL33-/-Treg suppressive properties and IFNγ production.

2. Deletion of IFNγR renders Tregs unresponsive to this destabilizing IFNγ and fails PD-1 checkpoint blockade immunotherapy.

		[37, 74]	
DCs	Antigen-presenting cells	1. Inflammatory DCs are required for Treg reprogramming, driving an acquisition of pro-inflammatory phenotype.

2. Tolerogenic tumor-associated DCs resist the inflammation-induced reprogramming of Tregs in vivo.

	1. Inflammatory DCs trigger IL-6 expression and cognate interaction with Tregs via MHC class II

2. Tolerogenic tumor-associated DCs express IDO, PD-L1, or semaphorin-4a to resist reprogramming. IDO blocks IL-6 production through effects on NF-IL6 (CEBP) or activating GCN2 pathway in Tregs phosphorylating the ribosomal translation factor eIF2 to alter ribosomal translation of mRNA species.

	[20, 163]	

Disappointingly, sometimes single or multiple blocking Treg-stabilizing signals aren’t sufficient to provide adequate anti-tumor immunity, and another possible approach would be in conjunction with active immunotherapy such as ICBs, chemotherapy, or radiation to elicit tumor killing. In I/II clinical models, the effectiveness of some IDO1 inhibitors (epacadostat, BMS-986205, KHK2455, and BGB-7204) in combination with PD-1 therapies has been demonstrated to alter the immunosuppressive environment around tumors by blocking Treg recruitment and reducing the number of Tregs in TIME, and whether this affects Treg reprogramming is unknown [170]. Unfortunately, phase 3 clinical trials of epacadostat didn’t show clinical benefit compared with pembrolizumab monotherapy in patients with advanced malignant melanoma [171]. Next, specific deletion of SCAP in Tregs reduces Pdcd1 (encoding PD-1) in combination with anti-PD-1 treatment as an effective immunotherapy. Although B16 melanoma was largely ineffective against PD-1 treatment, the absence of SCAP in Tregs sensitized mice to this immunotherapy [73]. Additionally, anti-CTLA4 checkpoint blockage raises EZH2 transcription within TIME and may facilitate the inhibitory function of TI-Tregs. Therefore, in murine cancer models, anti-CTLA4 and EZH2 inhibition could cooperate to provide strong anti-cancer immune responses [42]. Combination therapy based on synergistic mechanisms could overcome resistance to ICBs during immunotherapy. Furthermore, when Tregs are destabilized, the endogenous antigen cross-presentation could become strengthened thus promoting immune response to antigens produced by radiation and chemotherapy.

Solution of anti-PD-1 antibody resistance by Treg reprogramming

The anti-PD-1/PD-L1 antibodies offer the dawn of cancer treatment, but the issue of resistance has been a major concern, especially in the case of solid tumors where the effectiveness is limited. Studies have found that resistance is associated with genetic mutations, increased expression of other immune checkpoints such as TIM3 and CD38, lack of tumor antigens, and impaired function of effector T cells [107]. It appears that Tregs also exert an influence on the resistance to anti-PD-1 antibodies. Wen et al. validated in the accumulation of Tregs in TIME of mice resistant to anti-PD-1 antibody was significantly higher than that of mice sensitive to anti-PD-1 antibody [172]. Likewise, in a mouse model of head and neck squamous cell carcinoma, after the application of anti-PD-L1 antibody treatment, analysis of recurrent tumors revealed a marked increase in the proportion of Tregs. To further determine whether Tregs are involved in resistance to PD-1 treatment, researchers targeted deletion Tregs with anti-CD25 antibodies, which restored anti-PD-L1 antibody-mediated anti-tumor immunity and contributed to the rejection of established tumors [173]. In addition to counteracting the tumor-killing effect, an increase in immune suppression due to the lack of PD-1 signal transduction in Tregs may also lead to tumor progression similar to hyper-progressive disease [108], a severe cancer condition characterized by rapid tumor growth after immunotherapy [174–176]. Compared to chemotherapy (5.1%), the incidence of hyper-progressive disease in non-small cell lung cancer patients receiving anti-PD-1 treatment is higher (13.8%) [109]. Detailedly, Treg-induced resistance to ICBs includes upregulation of substitute checkpoint molecules like LAG-3 and TIM-3 in Tregs [177], and increased adenosine with strong immunosuppressive effects, derived from Tregs apoptotic during PD-1 therapy.

Tregs play a crucial role in the resistance to anti-PD-1/PD-L1 antibodies. Depleting or reprogramming Tregs may improve the effectiveness of anti-PD-1/PD-L1 antibodies, offering hope for alleviating the challenge of resistance. It has been demonstrated that most TI-Tregs lose their inhibitory function and produce IFNγ after disruption of the CBM complex. This enhances the efficacy of PD-1 blockade that would otherwise not respond to anti-PD-1 monotherapy [24]. Jacquelot and colleagues confirmed that pharmacological or genetic disruption of nitric oxide synthase 2 sustained PD-1 blockade for long-term control of tumors, through decreasing Treg and DC activation [178]. Including Treg depleted (anti-CTLA-4) or destabilized (EZH2 inhibitor), restores systemic immune state and PD-1 treatment responsiveness [179].

Future directions for TI-Tregs to improve research efficiency

The recent accelerated progress in nanodrug technology has yielded unique insights into the safety and long-term viability of cancer treatment. Many nanomedicines have been used to reduce Treg numbers and address Tregs, such as nanoscale formulations of paclitaxel and IL-2-conjugated nanoparticles. This means that we could leverage nanomedicines for precise delivery, enhanced cellular uptake, and other related benefits. Prospects for tailoring nanocarriers to administer Treg reprogramming agents hold promise for alleviating systemic toxicity and elevating drug concentrations within TIME [180]. Concurrently, it is imperative to exercise caution regarding the impact on other constituents within TIME.

Recently, state-of-the-art engineered 3D ex vivo models have the capability to replicate the intricate structures and functional characteristics of TIME, a dynamic ecological system. In contrast to conventional 2D cell culture assays and in vivo animal models utilized in cancer research, this platform presents no ethical concerns and effectively bridges the gap between oversimplified 2D systems and animal models. Notably, the composition of the TIME in animal models significantly differs from that in humans, and these models could more faithfully represent human tumor behavior. Consequently, they enhance our comprehension of cancer biology and facilitate the development of more efficacious treatment strategies, resulting in more precise and effective treatment outcomes. In recent years, the advent of engineered 3D ex vivo tissue models has markedly advanced the accurate modeling of human diseases, particularly cancer. Thus, tumor/organ-on-a-chip platforms, as more precise and realistic models, hold significant promise for investigating immune suppression mechanisms in individual TIME and Treg reprogramming therapies [181].

Conclusion

Tregs suppress immune responses and promote tumor development. Although countless researchers are conducting clinical studies on Tregs, the focus is on Treg depletion, and there is little research on Treg reprogramming and its link to tumor treatment lists the representative portions (Table 3).

Table 3 Representative Treg clinical trials for tumors

NCT Number	Phases	Study Status	Conditions	Interventions	Target name	Study Results	
NCT04158583	PHASE1	TERMINATED	Solid Tumors	DRUG: RO7296682	CD25	YES	
NCT01929486	PHASE1	UNKNOWN	Solid Tumor	BIOLOGICAL: Mogamulizumab	CCR4	NO	
NCT05537740	PHASE1	RECRUITING	Advanced Solid Tumors	DRUG: BAY3375968|DRUG: Pembrolizumab	CCR8	NO	
NCT01155505	PHASE1	UNKNOWN	Advanced Solid Tumors	DRUG: Lenalidomide (CC-5013)	--	NO	
NCT02705703	PHASE1|PHASE2	WITHDRAWN	Cancer|Metastatic Solid Malignancies	BIOLOGICAL: TAPA-pulsed DC vaccine	DCs	NO	
NCT03601611	NA	COMPLETED	Solid Tumor|Colitis|Arthritis	DRUG: Tocilizumab (RoACTEMRA)	IL-6	NO	
NCT02977156	PHASE1	COMPLETED	Metastatic Tumor|Advanced Tumor	BIOLOGICAL: Pexa-Vec|DRUG: Ipilimumab	CTLA4	NO	
NCT02946671	PHASE1	COMPLETED	Gastric Cancer|Esophageal Cancer|Lung Cancer|Renal Cancer|Oral Cancer	BIOLOGICAL: Mogamulizumab|BIOLOGICAL: Nivolumab	CCR4, PD-1	NO	
NCT02453620	PHASE1	ACTIVE_NOT_RECRUITING	Anatomic Stage III Breast Cancer AJCC v8|Anatomic Stage IV Breast Cancer AJCC v8|Breast Adenocarcinoma|Invasive Breast Carcinoma|Malignant Solid Neoplasm	PROCEDURE: Biopsy|OTHER: Blood Sample|PROCEDURE: Bone Scan|PROCEDURE: Computed Tomography|DRUG: Entinostat|BIOLOGICAL: Ipilimumab|BIOLOGICAL: Nivolumab|OTHER: Pharmacogenomic Study|OTHER: Pharmacological Study|PROCEDURE: Positron Emission Tomography	CCR4, PD-1	NO	
NCT05200559	PHASE1|PHASE2	RECRUITING	Epithelial Ovarian Cancer	DRUG: Pembrolizumab|DRUG: E7777	PD-1, CD25	NO	
NCT05469490	PHASE1	WITHDRAWN	Advanced Solid Tumors	RADIATION: Stereotactic Body Radiotherapy (SBRT)|DRUG: navoximod|DRUG: NLG802 (indoximod Prodrug)	--	NO	
NCT03421353	PHASE1	ACTIVE_NOT_RECRUITING	Advanced Solid Tumours	DRUG: AZD9150|DRUG: Durvalumab|DRUG: Cisplatin|DRUG: 5-Flourouracil|DRUG: Carboplatin|DRUG: Gemcitabine|DRUG: Nab-paclitaxel	PD-1, STAT3	NO	
NCT05537740	PHASE1	RECRUITING	Advanced Solid Tumors	DRUG: BAY3375968|DRUG: Pembrolizumab	CCR8	NO	
NCT00128622	PHASE1	COMPLETED	Breast Cancer|Colorectal Cancer|Lung Cancer|Pancreatic Cancer|Unspecified Adult Solid Tumor, Protocol Specific	BIOLOGICAL: denileukin diftitox|BIOLOGICAL: recombinant fowlpox-CEA(6D)/TRICOM vaccine|BIOLOGICAL: therapeutic autologous dendritic cells	CD25	NO	
NCT02404441	PHASE1|PHASE2	COMPLETED	Melanoma|Non-small Sell Lung Cancer (NSCLC)|Triple Negative Breast Cancer|Anaplastic Thyroid Cancer|Other Solid Tumors	BIOLOGICAL: PDR001	PD-1	YES	

It is effective to reprogram Tregs for the treatment of cancer, which not only impairs Treg suppression but also converts them into pro-inflammatory phenotypes constituting a novel source of anti-tumor effector activity. Tumors with low mutation load and neoantigen levels, such as CBM complex, aren’t easily recognized thus limiting immune activation. In contrast, the TCR pool of Tregs is favored for the recognition of self-antigens and doesn’t require neoantigenic epitopes to recognize tumor cells. Therefore, pro-inflammatory Tregs acquired after reprogramming perform a vital role in tumor-killing immune activation [37]. Moreover, many of the molecules described here aren’t exclusive to TI-Tregs, and the high similarity between Tregs and other lymphocytes makes the selectively targeted suppression of intratumor Tregs difficult. Targeting these pathways in other lymphocytes may occasionally benefit cancer immunotherapy, but it may also occasionally impede the activity of beneficial immune cells leading to antagonizing the anti-tumor response. When Treg reprogramming occurs in the periphery, systemic autoimmunity is triggered by interfering with the role of Tregs in maintaining peripheral homeostasis. Consequently, current and future challenges include determining which changes in factors selectively induce specific subpopulations of Tregs in TIME but have limited effects on peripheral Tregs, as well as similarly enhancing cancer immune responses when these changes occur in other cell types. Furthermore, the preclinical research in animal models or in vitro cellular served as the main foundation for this review. Although there are signs of undergoing Treg reprogramming in humans, it remains to be established whether this also applies to human tumors treated with immunotherapy. Tumor immunotherapy against Tregs remains both challenging and promising. To minimize the potential for severe adverse reactions and increase the relevance of research findings to human tumors, it is advisable to utilize advanced technologies such as nanoparticle delivery systems and innovative tumor/organ-on-a-chip platforms in the investigation of Treg reprogramming.

Acknowledgements

Not applicable.

Author contributions

ZQL, ZKZ, and XWH provided guidance throughout the preparation of this manuscript. JXX and ZKZ wrote the manuscript. ZKZ, JXX, STL, YYL, RQZ, and XZ reviewed and made significant revisions to the manuscript. YYZ, HX, SYW, ANZ, and YHB revised the manuscript. ZKZ and JXX collected and prepared the related papers. All authors read and approved the final manuscript.

Funding

This study was supported by The Henan Provincial Science and Technology Research Project (221100310100).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Abbreviations

TIME tumor immune microenvironment

Tregs regulatory T cells

ICBs immune checkpoint blockades

cTreg central regulatory T cell

eTreg effector regulatory T cell

nTreg natural regulatory T cell

iTreg induced regulatory T cell

TI-Treg tumor-infiltrating regulatory T cell

CTLA-4 cytotoxic T-lymphocyte-associated protein 4

PD-1 programmed death receptor 1

CTLs cytotoxic T lymphocytes

IFN interferon

Ezh2 enhancer of zeste homolog 2

Foxp3 Forkhead box protein P3

CNS Conserved non-coding sequence

TET ten-eleven translocation proteins

TNF tumor necrosis factor

Tfr Follicular regulatory T

Tfh T follicular helper

TIGIT T cell immunoglobulin and ITIM domain

CCR C-C Motif Chemokine Receptor

Blimp1 B lymphocyte-induced maturation protein 1

STAT signal transducers and activators of transduction

SREBPs Sterol regulatory element-binding proteins

SCAP SREBP cleavage-activation protein

PI3K Phosphoinositide 3-Kinase

IKZF2 IKAROS Family Zinc Finger 2

Nr4a nuclear receptor subfamily 4, group A

GITR glucocorticoid-induced TNFR-related gene

NF-κB nuclear factor kappa-B

mTOR mammalian target of rapamycin

AKT protein kinase, strain AK, Thymoma

Nrp-1 Neuropilin-1

PTEN phosphatase and tensin homolog deleted on chromosome ten

Sema4a semaphorin 4 A

CARD11 caspase recruitment domain 11

BCL10 B cell lymphoma/leukemia protein10

MALT1 Mucosa-­associated lymphoid tissue protein 1, also termed paracaspase 1

TRAF6 TNF receptor-associated factor 6

miRNAs/miRs microRNAs

lncRNAs long noncoding RNAs

Foxo1 forkhead box o1

IL interleukin

ROR RAR-related orphan nuclear receptor

IDO indoleamine 2,3 dioxygenase

DCs dendritic cells

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Zhaokai Zhou, Jiaxin Xu and Shutong Liu contributed equally to this work.
==== Refs
References

1. Zhang C Zhou L Li S Zhao J Meng X Ma L Wang Y Li C Zheng L Ming L Obesity accelerates immune evasion of non-small cell lung carcinoma via TFEB-dependent upregulation of Siglec-15 and glycolytic reprogramming Cancer Lett 2022 550 215918 10.1016/j.canlet.2022.215918 36150633
Zhang C, Zhou L, Li S, Zhao J, Meng X, Ma L, Wang Y, Li C, Zheng L, Ming L. Obesity accelerates immune evasion of non-small cell lung carcinoma via TFEB-dependent upregulation of Siglec-15 and glycolytic reprogramming. Cancer Lett. 2022;550:215918. 10.1016/j.canlet.2022.215918.36150633 10.1016/j.canlet.2022.215918
2. Ludmir EB McCaw ZR Grossberg AJ Wei LJ Fuller CD Quantifying the benefit of non-small-cell lung cancer immunotherapy Lancet 2019 394 1904 10.1016/s0140-6736(19)32503-6 31777387
Ludmir EB, McCaw ZR, Grossberg AJ, Wei LJ, Fuller CD. Quantifying the benefit of non-small-cell lung cancer immunotherapy. Lancet. 2019;394:1904. 10.1016/s0140-6736(19)32503-6.31777387 10.1016/s0140-6736(19)32503-6
3. Peng H Wu X Zhong R Yu T Cai X Liu J Wen Y Ao Y Chen J Li Y Profiling Tumor Immune Microenvironment of Non-small Cell Lung Cancer using multiplex immunofluorescence Front Immunol 2021 12 750046 10.3389/fimmu.2021.750046 34804034
Peng H, Wu X, Zhong R, Yu T, Cai X, Liu J, Wen Y, Ao Y, Chen J, Li Y, et al. Profiling Tumor Immune Microenvironment of Non-small Cell Lung Cancer using multiplex immunofluorescence. Front Immunol. 2021;12:750046. 10.3389/fimmu.2021.750046.34804034 10.3389/fimmu.2021.750046
4. Wang ES Verano AL Nowak RP Yuan JC Donovan KA Eleuteri NA Yue H Ngo KH Lizotte PH Gokhale PC Acute pharmacological degradation of Helios destabilizes regulatory T cells Nat Chem Biol 2021 17 711 7 10.1038/s41589-021-00802-w 34035522
Wang ES, Verano AL, Nowak RP, Yuan JC, Donovan KA, Eleuteri NA, Yue H, Ngo KH, Lizotte PH, Gokhale PC, et al. Acute pharmacological degradation of Helios destabilizes regulatory T cells. Nat Chem Biol. 2021;17:711–7. 10.1038/s41589-021-00802-w.34035522 10.1038/s41589-021-00802-w
5. Ji D, Song C, Li Y, Xia J, Wu Y, Jia J, Cui X, Yu S, Gu J. Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer. J Immunother Cancer. 2020;8. 10.1136/jitc-2020-000826.
6. Li C Jiang P Wei S Xu X Wang J Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects Mol Cancer 2020 19 116 10.1186/s12943-020-01234-1 32680511
Li C, Jiang P, Wei S, Xu X, Wang J. Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects. Mol Cancer. 2020;19:116. 10.1186/s12943-020-01234-1.32680511 10.1186/s12943-020-01234-1
7. Toomer KH, Malek TR. Cytokine Signaling in the Development and Homeostasis of Regulatory T Cells. Cold Spring Harb Perspect Biol. 2018;10. 10.1101/cshperspect.a028597.
8. Maj T Wang W Crespo J Zhang H Wang W Wei S Zhao L Vatan L Shao I Szeliga W Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor Nat Immunol 2017 18 1332 41 10.1038/ni.3868 29083399
Maj T, Wang W, Crespo J, Zhang H, Wang W, Wei S, Zhao L, Vatan L, Shao I, Szeliga W, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol. 2017;18:1332–41. 10.1038/ni.3868.29083399 10.1038/ni.3868
9. Budhu S, Schaer DA, Li Y, Toledo-Crow R, Panageas K, Yang X, Zhong H, Houghton AN, Silverstein SC, Merghoub T, et al. Blockade of surface-bound TGF-β on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci Signal. 2017;10. 10.1126/scisignal.aak9702.
10. Kalia V Penny LA Yuzefpolskiy Y Baumann FM Sarkar S Quiescence of memory CD8(+) T cells is mediated by Regulatory T Cells through inhibitory receptor CTLA-4 Immunity 2015 42 1116 29 10.1016/j.immuni.2015.05.023 26084026
Kalia V, Penny LA, Yuzefpolskiy Y, Baumann FM, Sarkar S. Quiescence of memory CD8(+) T cells is mediated by Regulatory T Cells through inhibitory receptor CTLA-4. Immunity. 2015;42:1116–29. 10.1016/j.immuni.2015.05.023.26084026 10.1016/j.immuni.2015.05.023
11. Sarhan D Hippen KL Lemire A Hying S Luo X Lenvik T Curtsinger J Davis Z Zhang B Cooley S Adaptive NK cells resist Regulatory T-cell suppression driven by IL37 Cancer Immunol Res 2018 6 766 75 10.1158/2326-6066.Cir-17-0498 29784636
Sarhan D, Hippen KL, Lemire A, Hying S, Luo X, Lenvik T, Curtsinger J, Davis Z, Zhang B, Cooley S, et al. Adaptive NK cells resist Regulatory T-cell suppression driven by IL37. Cancer Immunol Res. 2018;6:766–75. 10.1158/2326-6066.Cir-17-0498.29784636 10.1158/2326-6066.Cir-17-0498
12. Kim JH Kim BS Lee SK Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy Immune Netw 2020 20 e4 10.4110/in.2020.20.e4 32158592
Kim JH, Kim BS, Lee SK. Regulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy. Immune Netw. 2020;20:e4. 10.4110/in.2020.20.e4.32158592 10.4110/in.2020.20.e4
13. Carmenate T Ortíz Y Enamorado M García-Martínez K Avellanet J Moreno E Graça L León K Blocking IL-2 Signal in Vivo with an IL-2 antagonist reduces Tumor Growth through the Control of Regulatory T Cells J Immunol 2018 200 3475 84 10.4049/jimmunol.1700433 29618524
Carmenate T, Ortíz Y, Enamorado M, García-Martínez K, Avellanet J, Moreno E, Graça L, León K. Blocking IL-2 Signal in Vivo with an IL-2 antagonist reduces Tumor Growth through the Control of Regulatory T Cells. J Immunol. 2018;200:3475–84. 10.4049/jimmunol.1700433.29618524 10.4049/jimmunol.1700433
14. Toomer KH Yuan X Yang J Dee MJ Yu A Malek TR Developmental Progression and Interrelationship of Central and Effector Regulatory T cell subsets J Immunol 2016 196 3665 76 10.4049/jimmunol.1500595 27009492
Toomer KH, Yuan X, Yang J, Dee MJ, Yu A, Malek TR. Developmental Progression and Interrelationship of Central and Effector Regulatory T cell subsets. J Immunol. 2016;196:3665–76. 10.4049/jimmunol.1500595.27009492 10.4049/jimmunol.1500595
15. Yang D Zhao X Lin X Bcl10 is required for the development and suppressive function of Foxp3(+) regulatory T cells Cell Mol Immunol 2021 18 206 18 10.1038/s41423-019-0297-y 31595055
Yang D, Zhao X, Lin X. Bcl10 is required for the development and suppressive function of Foxp3(+) regulatory T cells. Cell Mol Immunol. 2021;18:206–18. 10.1038/s41423-019-0297-y.31595055 10.1038/s41423-019-0297-y
16. Zhang H Xia N Tang T Nie S Zha L Zhang M Lv B Lu Y Jiao J Li J Cholesterol suppresses human iTreg differentiation and nTreg function through mitochondria-related mechanisms J Transl Med 2023 21 224 10.1186/s12967-023-03896-z 36973679
Zhang H, Xia N, Tang T, Nie S, Zha L, Zhang M, Lv B, Lu Y, Jiao J, Li J, et al. Cholesterol suppresses human iTreg differentiation and nTreg function through mitochondria-related mechanisms. J Transl Med. 2023;21:224. 10.1186/s12967-023-03896-z.36973679 10.1186/s12967-023-03896-z
17. Käser T Mair KH Hammer SE Gerner W Saalmüller A Natural and inducible Tregs in swine: Helios expression and functional properties Dev Comp Immunol 2015 49 323 31 10.1016/j.dci.2014.12.005 25511662
Käser T, Mair KH, Hammer SE, Gerner W, Saalmüller A. Natural and inducible Tregs in swine: Helios expression and functional properties. Dev Comp Immunol. 2015;49:323–31. 10.1016/j.dci.2014.12.005.25511662 10.1016/j.dci.2014.12.005
18. Yang J Wei P Barbi J Huang Q Yang E Bai Y Nie J Gao Y Tao J Lu Y The deubiquitinase USP44 promotes Treg function during inflammation by preventing FOXP3 degradation EMBO Rep 2020 21 e50308 10.15252/embr.202050308 32644293
Yang J, Wei P, Barbi J, Huang Q, Yang E, Bai Y, Nie J, Gao Y, Tao J, Lu Y, et al. The deubiquitinase USP44 promotes Treg function during inflammation by preventing FOXP3 degradation. EMBO Rep. 2020;21:e50308. 10.15252/embr.202050308.32644293 10.15252/embr.202050308
19. Schmidt A Oberle N Krammer PH Molecular mechanisms of treg-mediated T cell suppression Front Immunol 2012 3 51 10.3389/fimmu.2012.00051 22566933
Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of treg-mediated T cell suppression. Front Immunol. 2012;3:51. 10.3389/fimmu.2012.00051.22566933 10.3389/fimmu.2012.00051
20. Munn DH Indoleamine 2,3-dioxygenase, Tregs and cancer Curr Med Chem 2011 18 2240 6 10.2174/092986711795656045 21517755
Munn DH. Indoleamine 2,3-dioxygenase, Tregs and cancer. Curr Med Chem. 2011;18:2240–6. 10.2174/092986711795656045.21517755 10.2174/092986711795656045
21. Liu Y Wang L Predina J Han R Beier UH Wang LC Kapoor V Bhatti TR Akimova T Singhal S Inhibition of p300 impairs Foxp3⁺ T regulatory cell function and promotes antitumor immunity Nat Med 2013 19 1173 7 10.1038/nm.3286 23955711
Liu Y, Wang L, Predina J, Han R, Beier UH, Wang LC, Kapoor V, Bhatti TR, Akimova T, Singhal S, et al. Inhibition of p300 impairs Foxp3⁺ T regulatory cell function and promotes antitumor immunity. Nat Med. 2013;19:1173–7. 10.1038/nm.3286.23955711 10.1038/nm.3286
22. Wang H Franco F Ho PC Metabolic regulation of Tregs in Cancer: opportunities for Immunotherapy Trends Cancer 2017 3 583 92 10.1016/j.trecan.2017.06.005 28780935
Wang H, Franco F, Ho PC. Metabolic regulation of Tregs in Cancer: opportunities for Immunotherapy. Trends Cancer. 2017;3:583–92. 10.1016/j.trecan.2017.06.005.28780935 10.1016/j.trecan.2017.06.005
23. Munn DH Sharma MD Johnson TS Treg destabilization and reprogramming: implications for Cancer Immunotherapy Cancer Res 2018 78 5191 9 10.1158/0008-5472.Can-18-1351 30181177
Munn DH, Sharma MD, Johnson TS. Treg destabilization and reprogramming: implications for Cancer Immunotherapy. Cancer Res. 2018;78:5191–9. 10.1158/0008-5472.Can-18-1351.30181177 10.1158/0008-5472.Can-18-1351
24. Di Pilato M Kim EY Cadilha BL Prüßmann JN Nasrallah MN Seruggia D Usmani SM Misale S Zappulli V Carrizosa E Targeting the CBM complex causes T(reg) cells to prime tumours for immune checkpoint therapy Nature 2019 570 112 6 10.1038/s41586-019-1215-2 31092922
Di Pilato M, Kim EY, Cadilha BL, Prüßmann JN, Nasrallah MN, Seruggia D, Usmani SM, Misale S, Zappulli V, Carrizosa E, et al. Targeting the CBM complex causes T(reg) cells to prime tumours for immune checkpoint therapy. Nature. 2019;570:112–6. 10.1038/s41586-019-1215-2.31092922 10.1038/s41586-019-1215-2
25. Litzinger MT Fernando R Curiel TJ Grosenbach DW Schlom J Palena C IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity Blood 2007 110 3192 201 10.1182/blood-2007-06-094615 17616639
Litzinger MT, Fernando R, Curiel TJ, Grosenbach DW, Schlom J, Palena C. IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood. 2007;110:3192–201. 10.1182/blood-2007-06-094615.17616639 10.1182/blood-2007-06-094615
26. Li Y Tang D Yin L Dai Y New insights for regulatory T cell in lupus nephritis Autoimmun Rev 2022 21 103134 10.1016/j.autrev.2022.103134 35690245
Li Y, Tang D, Yin L, Dai Y. New insights for regulatory T cell in lupus nephritis. Autoimmun Rev. 2022;21:103134. 10.1016/j.autrev.2022.103134.35690245 10.1016/j.autrev.2022.103134
27. Marfil-Garza BA Pawlick RL Szeto J Kroger C Tahiliani V Hefler J Dadheech N Seavey MM Wolf J Jasuja RR Tumor necrosis factor receptor superfamily member 25 (TNFRSF25) agonists in islet transplantation: endogenous in vivo regulatory T cell expansion promotes prolonged allograft survival Am J Transpl 2022 22 1101 14 10.1111/ajt.16940
Marfil-Garza BA, Pawlick RL, Szeto J, Kroger C, Tahiliani V, Hefler J, Dadheech N, Seavey MM, Wolf J, Jasuja RR, et al. Tumor necrosis factor receptor superfamily member 25 (TNFRSF25) agonists in islet transplantation: endogenous in vivo regulatory T cell expansion promotes prolonged allograft survival. Am J Transpl. 2022;22:1101–14. 10.1111/ajt.16940.10.1111/ajt.16940
28. Tanaka A Sakaguchi S Regulatory T cells in cancer immunotherapy Cell Res 2017 27 109 18 10.1038/cr.2016.151 27995907
Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017;27:109–18. 10.1038/cr.2016.151.27995907 10.1038/cr.2016.151
29. Liu JY Wu Y Zhang XS Yang JL Li HL Mao YQ Wang Y Cheng X Li YQ Xia JC Single administration of low dose cyclophosphamide augments the antitumor effect of dendritic cell vaccine Cancer Immunol Immunother 2007 56 1597 604 10.1007/s00262-007-0305-4 17440723
Liu JY, Wu Y, Zhang XS, Yang JL, Li HL, Mao YQ, Wang Y, Cheng X, Li YQ, Xia JC, et al. Single administration of low dose cyclophosphamide augments the antitumor effect of dendritic cell vaccine. Cancer Immunol Immunother. 2007;56:1597–604. 10.1007/s00262-007-0305-4.17440723 10.1007/s00262-007-0305-4
30. Jiang W Cai G Hu P Wang Y Personalized medicine of non-gene-specific chemotherapies for non-small cell lung cancer Acta Pharm Sin B 2021 11 3406 16 10.1016/j.apsb.2021.02.003 34900526
Jiang W, Cai G, Hu P, Wang Y. Personalized medicine of non-gene-specific chemotherapies for non-small cell lung cancer. Acta Pharm Sin B. 2021;11:3406–16. 10.1016/j.apsb.2021.02.003.34900526 10.1016/j.apsb.2021.02.003
31. Li Q Han J Yang Y Chen Y PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy Front Immunol 2022 13 1070961 10.3389/fimmu.2022.1070961 36601120
Li Q, Han J, Yang Y, Chen Y. PD-1/PD-L1 checkpoint inhibitors in advanced hepatocellular carcinoma immunotherapy. Front Immunol. 2022;13:1070961. 10.3389/fimmu.2022.1070961.36601120 10.3389/fimmu.2022.1070961
32. Füchsl F, Krackhardt AM. Paving the way to solid tumors: challenges and strategies for Adoptively Transferred Transgenic T Cells in the Tumor Microenvironment. Cancers (Basel). 2022;14. 10.3390/cancers14174192.
33. Obradovic A Ager C Turunen M Nirschl T Khosravi-Maharlooei M Iuga A Jackson CM Yegnasubramanian S Tomassoni L Fernandez EC Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators Cancer Cell 2023 41 933 e949911 10.1016/j.ccell.2023.04.003 37116491
Obradovic A, Ager C, Turunen M, Nirschl T, Khosravi-Maharlooei M, Iuga A, Jackson CM, Yegnasubramanian S, Tomassoni L, Fernandez EC, et al. Systematic elucidation and pharmacological targeting of tumor-infiltrating regulatory T cell master regulators. Cancer Cell. 2023;41:933–e949911. 10.1016/j.ccell.2023.04.003.37116491 10.1016/j.ccell.2023.04.003
34. Kidani Y, Nogami W, Yasumizu Y, Kawashima A, Tanaka A, Sonoda Y, Tona Y, Nashiki K, Matsumoto R, Hagiwara M, et al. CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory. Proc Natl Acad Sci U S A. 2022;119. 10.1073/pnas.2114282119.
35. Joshi NS Akama-Garren EH Lu Y Lee DY Chang GP Li A DuPage M Tammela T Kerper NR Farago AF Regulatory T cells in Tumor-Associated Tertiary lymphoid structures suppress anti-tumor T cell responses Immunity 2015 43 579 90 10.1016/j.immuni.2015.08.006 26341400
Joshi NS, Akama-Garren EH, Lu Y, Lee DY, Chang GP, Li A, DuPage M, Tammela T, Kerper NR, Farago AF, et al. Regulatory T cells in Tumor-Associated Tertiary lymphoid structures suppress anti-tumor T cell responses. Immunity. 2015;43:579–90. 10.1016/j.immuni.2015.08.006.26341400 10.1016/j.immuni.2015.08.006
36. Pacholczyk R Kern J The T-cell receptor repertoire of regulatory T cells Immunology 2008 125 450 8 10.1111/j.1365-2567.2008.02992.x 19128356
Pacholczyk R, Kern J. The T-cell receptor repertoire of regulatory T cells. Immunology. 2008;125:450–8. 10.1111/j.1365-2567.2008.02992.x.19128356 10.1111/j.1365-2567.2008.02992.x
37. Amoozgar Z Kloepper J Ren J Tay RE Kazer SW Kiner E Krishnan S Posada JM Ghosh M Mamessier E Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas Nat Commun 2021 12 2582 10.1038/s41467-021-22885-8 33976133
Amoozgar Z, Kloepper J, Ren J, Tay RE, Kazer SW, Kiner E, Krishnan S, Posada JM, Ghosh M, Mamessier E, et al. Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas. Nat Commun. 2021;12:2582. 10.1038/s41467-021-22885-8.33976133 10.1038/s41467-021-22885-8
38. Ohue Y Nishikawa H Regulatory T Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci 2019 110 2080 9 10.1111/cas.14069 31102428
Ohue Y, Nishikawa H, Regulatory T. (Treg) cells in cancer: can Treg cells be a new therapeutic target? Cancer Sci. 2019;110:2080–9. 10.1111/cas.14069.31102428 10.1111/cas.14069
39. Moreno Ayala MA Li Z DuPage M Treg programming and therapeutic reprogramming in cancer Immunology 2019 157 198 209 10.1111/imm.13058 30866047
Moreno Ayala MA, Li Z, DuPage M. Treg programming and therapeutic reprogramming in cancer. Immunology. 2019;157:198–209. 10.1111/imm.13058.30866047 10.1111/imm.13058
40. Inukai S Kock KH Bulyk ML Transcription factor-DNA binding: beyond binding site motifs Curr Opin Genet Dev 2017 43 110 9 10.1016/j.gde.2017.02.007 28359978
Inukai S, Kock KH, Bulyk ML. Transcription factor-DNA binding: beyond binding site motifs. Curr Opin Genet Dev. 2017;43:110–9. 10.1016/j.gde.2017.02.007.28359978 10.1016/j.gde.2017.02.007
41. Sharma MD Hou DY Baban B Koni PA He Y Chandler PR Blazar BR Mellor AL Munn DH Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice Immunity 2010 33 942 54 10.1016/j.immuni.2010.11.022 21145762
Sharma MD, Hou DY, Baban B, Koni PA, He Y, Chandler PR, Blazar BR, Mellor AL, Munn DH. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity. 2010;33:942–54. 10.1016/j.immuni.2010.11.022.21145762 10.1016/j.immuni.2010.11.022
42. Wang D Quiros J Mahuron K Pai CC Ranzani V Young A Silveria S Harwin T Abnousian A Pagani M Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer immunity Cell Rep 2018 23 3262 74 10.1016/j.celrep.2018.05.050 29898397
Wang D, Quiros J, Mahuron K, Pai CC, Ranzani V, Young A, Silveria S, Harwin T, Abnousian A, Pagani M, et al. Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer immunity. Cell Rep. 2018;23:3262–74. 10.1016/j.celrep.2018.05.050.29898397 10.1016/j.celrep.2018.05.050
43. Yates K Bi K Haining WN Cantor H Kim HJ Comparative transcriptome analysis reveals distinct genetic modules associated with helios expression in intratumoral regulatory T cells Proc Natl Acad Sci U S A 2018 115 2162 7 10.1073/pnas.1720447115 29440380
Yates K, Bi K, Haining WN, Cantor H, Kim HJ. Comparative transcriptome analysis reveals distinct genetic modules associated with helios expression in intratumoral regulatory T cells. Proc Natl Acad Sci U S A. 2018;115:2162–7. 10.1073/pnas.1720447115.29440380 10.1073/pnas.1720447115
44. Magnuson AM Kiner E Ergun A Park JS Asinovski N Ortiz-Lopez A Kilcoyne A Paoluzzi-Tomada E Weissleder R Mathis D Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types Proc Natl Acad Sci U S A 2018 115 E10672 81 10.1073/pnas.1810580115 30348759
Magnuson AM, Kiner E, Ergun A, Park JS, Asinovski N, Ortiz-Lopez A, Kilcoyne A, Paoluzzi-Tomada E, Weissleder R, Mathis D, et al. Identification and validation of a tumor-infiltrating Treg transcriptional signature conserved across species and tumor types. Proc Natl Acad Sci U S A. 2018;115:E10672–81. 10.1073/pnas.1810580115.30348759 10.1073/pnas.1810580115
45. Rudensky AY Regulatory T cells and Foxp3 Immunol Rev 2011 241 260 8 10.1111/j.1600-065X.2011.01018.x 21488902
Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev. 2011;241:260–8. 10.1111/j.1600-065X.2011.01018.x.21488902 10.1111/j.1600-065X.2011.01018.x
46. Fontenot JD Gavin MA Rudensky AY Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells Nat Immunol 2003 4 330 6 10.1038/ni904 12612578
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells. Nat Immunol. 2003;4:330–6. 10.1038/ni904.12612578 10.1038/ni904
47. Hori S Nomura T Sakaguchi S Control of regulatory T cell development by the transcription factor Foxp3 Science 2003 299 1057 61 10.1126/science.1079490 12522256
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61. 10.1126/science.1079490.12522256 10.1126/science.1079490
48. Komatsu N Mariotti-Ferrandiz ME Wang Y Malissen B Waldmann H Hori S Heterogeneity of natural Foxp3 + T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity Proc Natl Acad Sci U S A 2009 106 1903 8 10.1073/pnas.0811556106 19174509
Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S. Heterogeneity of natural Foxp3 + T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci U S A. 2009;106:1903–8. 10.1073/pnas.0811556106.19174509 10.1073/pnas.0811556106
49. Samstein RM Arvey A Josefowicz SZ Peng X Reynolds A Sandstrom R Neph S Sabo P Kim JM Liao W Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification Cell 2012 151 153 66 10.1016/j.cell.2012.06.053 23021222
Samstein RM, Arvey A, Josefowicz SZ, Peng X, Reynolds A, Sandstrom R, Neph S, Sabo P, Kim JM, Liao W, et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell. 2012;151:153–66. 10.1016/j.cell.2012.06.053.23021222 10.1016/j.cell.2012.06.053
50. Fontenot JD Rasmussen JP Williams LM Dooley JL Farr AG Rudensky AY Regulatory T cell lineage specification by the forkhead transcription factor foxp3 Immunity 2005 22 329 41 10.1016/j.immuni.2005.01.016 15780990
Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005;22:329–41. 10.1016/j.immuni.2005.01.016.15780990 10.1016/j.immuni.2005.01.016
51. Lahl K Mayer CT Bopp T Huehn J Loddenkemper C Eberl G Wirnsberger G Dornmair K Geffers R Schmitt E Nonfunctional regulatory T cells and defective control of Th2 cytokine production in natural scurfy mutant mice J Immunol 2009 183 5662 72 10.4049/jimmunol.0803762 19812199
Lahl K, Mayer CT, Bopp T, Huehn J, Loddenkemper C, Eberl G, Wirnsberger G, Dornmair K, Geffers R, Schmitt E, et al. Nonfunctional regulatory T cells and defective control of Th2 cytokine production in natural scurfy mutant mice. J Immunol. 2009;183:5662–72. 10.4049/jimmunol.0803762.19812199 10.4049/jimmunol.0803762
52. Yang XO Nurieva R Martinez GJ Kang HS Chung Y Pappu BP Shah B Chang SH Schluns KS Watowich SS Molecular antagonism and plasticity of regulatory and inflammatory T cell programs Immunity 2008 29 44 56 10.1016/j.immuni.2008.05.007 18585065
Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity. 2008;29:44–56. 10.1016/j.immuni.2008.05.007.18585065 10.1016/j.immuni.2008.05.007
53. Zheng Y Josefowicz S Chaudhry A Peng XP Forbush K Rudensky AY Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate Nature 2010 463 808 12 10.1038/nature08750 20072126
Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. 2010;463:808–12. 10.1038/nature08750.20072126 10.1038/nature08750
54. Manrique-Rincón AJ Ruas LP Fogagnolo CT Brenneman RJ Berezhnoy A Castelucci B Consonni SR Gilboa E Bajgelman MC Aptamer-mediated transcriptional gene silencing of Fox p 3 inhibits regulatory T cells and potentiates antitumor response Mol Ther Nucleic Acids 2021 25 143 51 10.1016/j.omtn.2021.05.005 34457999
Manrique-Rincón AJ, Ruas LP, Fogagnolo CT, Brenneman RJ, Berezhnoy A, Castelucci B, Consonni SR, Gilboa E, Bajgelman MC. Aptamer-mediated transcriptional gene silencing of Fox p 3 inhibits regulatory T cells and potentiates antitumor response. Mol Ther Nucleic Acids. 2021;25:143–51. 10.1016/j.omtn.2021.05.005.34457999 10.1016/j.omtn.2021.05.005
55. Li J Xu B He M Zong X Cunningham T Sha C Fan Y Cross R Hanna JH Feng Y Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation Cell Rep 2021 37 110124 10.1016/j.celrep.2021.110124 34910919
Li J, Xu B, He M, Zong X, Cunningham T, Sha C, Fan Y, Cross R, Hanna JH, Feng Y. Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation. Cell Rep. 2021;37:110124. 10.1016/j.celrep.2021.110124.34910919 10.1016/j.celrep.2021.110124
56. Yue X Trifari S Äijö T Tsagaratou A Pastor WA Zepeda-Martínez JA Lio CW Li X Huang Y Vijayanand P Control of Foxp3 stability through modulation of TET activity J Exp Med 2016 213 377 97 10.1084/jem.20151438 26903244
Yue X, Trifari S, Äijö T, Tsagaratou A, Pastor WA, Zepeda-Martínez JA, Lio CW, Li X, Huang Y, Vijayanand P, et al. Control of Foxp3 stability through modulation of TET activity. J Exp Med. 2016;213:377–97. 10.1084/jem.20151438.26903244 10.1084/jem.20151438
57. Fraietta JA Nobles CL Sammons MA Lundh S Carty SA Reich TJ Cogdill AP Morrissette JJD DeNizio JE Reddy S Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells Nature 2018 558 307 12 10.1038/s41586-018-0178-z 29849141
Fraietta JA, Nobles CL, Sammons MA, Lundh S, Carty SA, Reich TJ, Cogdill AP, Morrissette JJD, DeNizio JE, Reddy S, et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature. 2018;558:307–12. 10.1038/s41586-018-0178-z.29849141 10.1038/s41586-018-0178-z
58. Ghosh S Taylor A Chin M Huang HR Conery AR Mertz JA Salmeron A Dakle PJ Mele D Cote A Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition J Biol Chem 2016 291 13014 27 10.1074/jbc.M115.708560 27056325
Ghosh S, Taylor A, Chin M, Huang HR, Conery AR, Mertz JA, Salmeron A, Dakle PJ, Mele D, Cote A, et al. Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition. J Biol Chem. 2016;291:13014–27. 10.1074/jbc.M115.708560.27056325 10.1074/jbc.M115.708560
59. da Silva Martins M Piccirillo CA Functional stability of Foxp3 + regulatory T cells Trends Mol Med 2012 18 454 62 10.1016/j.molmed.2012.06.001 22771168
da Silva Martins M, Piccirillo CA. Functional stability of Foxp3 + regulatory T cells. Trends Mol Med. 2012;18:454–62. 10.1016/j.molmed.2012.06.001.22771168 10.1016/j.molmed.2012.06.001
60. Cretney E Kallies A Nutt SL Differentiation and function of Foxp3(+) effector regulatory T cells Trends Immunol 2013 34 74 80 10.1016/j.it.2012.11.002 23219401
Cretney E, Kallies A, Nutt SL. Differentiation and function of Foxp3(+) effector regulatory T cells. Trends Immunol. 2013;34:74–80. 10.1016/j.it.2012.11.002.23219401 10.1016/j.it.2012.11.002
61. Dixon ML Luo L Ghosh S Grimes JM Leavenworth JD Leavenworth JW Remodeling of the tumor microenvironment via disrupting Blimp1(+) effector Treg activity augments response to anti-PD-1 blockade Mol Cancer 2021 20 150 10.1186/s12943-021-01450-3 34798898
Dixon ML, Luo L, Ghosh S, Grimes JM, Leavenworth JD, Leavenworth JW. Remodeling of the tumor microenvironment via disrupting Blimp1(+) effector Treg activity augments response to anti-PD-1 blockade. Mol Cancer. 2021;20:150. 10.1186/s12943-021-01450-3.34798898 10.1186/s12943-021-01450-3
62. Cao Y Hou Y Zhao L Huang Y Liu G New insights into follicular regulatory T cells in the intestinal and tumor microenvironments J Cell Physiol 2023 238 1465 77 10.1002/jcp.31039 37210730
Cao Y, Hou Y, Zhao L, Huang Y, Liu G. New insights into follicular regulatory T cells in the intestinal and tumor microenvironments. J Cell Physiol. 2023;238:1465–77. 10.1002/jcp.31039.37210730 10.1002/jcp.31039
63. Shen E Rabe H Luo L Wang L Wang Q Yin J Yang X Liu W Sido JM Nakagawa H Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 transcription factor Cell Rep 2019 29 1848 e18611846 10.1016/j.celrep.2019.10.012 31722202
Shen E, Rabe H, Luo L, Wang L, Wang Q, Yin J, Yang X, Liu W, Sido JM, Nakagawa H, et al. Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 transcription factor. Cell Rep. 2019;29:1848–e18611846. 10.1016/j.celrep.2019.10.012.31722202 10.1016/j.celrep.2019.10.012
64. Garg G Muschaweckh A Moreno H Vasanthakumar A Floess S Lepennetier G Oellinger R Zhan Y Regen T Hiltensperger M Blimp1 prevents methylation of Foxp3 and Loss of Regulatory T Cell Identity at sites of inflammation Cell Rep 2019 26 1854 e18681855 10.1016/j.celrep.2019.01.070 30759395
Garg G, Muschaweckh A, Moreno H, Vasanthakumar A, Floess S, Lepennetier G, Oellinger R, Zhan Y, Regen T, Hiltensperger M, et al. Blimp1 prevents methylation of Foxp3 and Loss of Regulatory T Cell Identity at sites of inflammation. Cell Rep. 2019;26:1854–e18681855. 10.1016/j.celrep.2019.01.070.30759395 10.1016/j.celrep.2019.01.070
65. Luo L Hu X Dixon ML Pope BJ Leavenworth JD Raman C Meador WR Leavenworth JW Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis J Neuroinflammation 2021 18 27 10.1186/s12974-021-02076-4 33468194
Luo L, Hu X, Dixon ML, Pope BJ, Leavenworth JD, Raman C, Meador WR, Leavenworth JW. Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis. J Neuroinflammation. 2021;18:27. 10.1186/s12974-021-02076-4.33468194 10.1186/s12974-021-02076-4
66. Shen E Rabe H Luo L Wang L Wang Q Yin J Yang X Liu W Sido JM Nakagawa H Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 transcription factor Cell Rep 2020 31 107575 10.1016/j.celrep.2020.107575 32348761
Shen E, Rabe H, Luo L, Wang L, Wang Q, Yin J, Yang X, Liu W, Sido JM, Nakagawa H, et al. Control of Germinal Center Localization and Lineage Stability of Follicular Regulatory T Cells by the Blimp1 transcription factor. Cell Rep. 2020;31:107575. 10.1016/j.celrep.2020.107575.32348761 10.1016/j.celrep.2020.107575
67. Yabe D Brown MS Goldstein JL Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins Proc Natl Acad Sci U S A 2002 99 12753 8 10.1073/pnas.162488899 12242332
Yabe D, Brown MS, Goldstein JL. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci U S A. 2002;99:12753–8. 10.1073/pnas.162488899.12242332 10.1073/pnas.162488899
68. Yang T Espenshade PJ Wright ME Yabe D Gong Y Aebersold R Goldstein JL Brown MS Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER Cell 2002 110 489 500 10.1016/s0092-8674(02)00872-3 12202038
Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell. 2002;110:489–500. 10.1016/s0092-8674(02)00872-3.12202038 10.1016/s0092-8674(02)00872-3
69. Brown MS Radhakrishnan A Goldstein JL Retrospective on cholesterol homeostasis: the Central Role of Scap Annu Rev Biochem 2018 87 783 807 10.1146/annurev-biochem-062917-011852 28841344
Brown MS, Radhakrishnan A, Goldstein JL. Retrospective on cholesterol homeostasis: the Central Role of Scap. Annu Rev Biochem. 2018;87:783–807. 10.1146/annurev-biochem-062917-011852.28841344 10.1146/annurev-biochem-062917-011852
70. Goldstein JL DeBose-Boyd RA Brown MS Protein sensors for membrane sterols Cell 2006 124 35 46 10.1016/j.cell.2005.12.022 16413480
Goldstein JL, DeBose-Boyd RA, Brown MS. Protein sensors for membrane sterols. Cell. 2006;124:35–46. 10.1016/j.cell.2005.12.022.16413480 10.1016/j.cell.2005.12.022
71. Röhrig F Schulze A The multifaceted roles of fatty acid synthesis in cancer Nat Rev Cancer 2016 16 732 49 10.1038/nrc.2016.89 27658529
Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16:732–49. 10.1038/nrc.2016.89.27658529 10.1038/nrc.2016.89
72. Shimano H Sato R SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology Nat Rev Endocrinol 2017 13 710 30 10.1038/nrendo.2017.91 28849786
Shimano H, Sato R. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology. Nat Rev Endocrinol. 2017;13:710–30. 10.1038/nrendo.2017.91.28849786 10.1038/nrendo.2017.91
73. Lim SA Wei J Nguyen TM Shi H Su W Palacios G Dhungana Y Chapman NM Long L Saravia J Lipid signalling enforces functional specialization of T(reg) cells in tumours Nature 2021 591 306 11 10.1038/s41586-021-03235-6 33627871
Lim SA, Wei J, Nguyen TM, Shi H, Su W, Palacios G, Dhungana Y, Chapman NM, Long L, Saravia J, et al. Lipid signalling enforces functional specialization of T(reg) cells in tumours. Nature. 2021;591:306–11. 10.1038/s41586-021-03235-6.33627871 10.1038/s41586-021-03235-6
74. Overacre-Delgoffe AE Chikina M Dadey RE Yano H Brunazzi EA Shayan G Horne W Moskovitz JM Kolls JK Sander C Interferon-γ drives T(reg) fragility to promote anti-tumor immunity Cell 2017 169 1130 e11411111 10.1016/j.cell.2017.05.005 28552348
Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, et al. Interferon-γ drives T(reg) fragility to promote anti-tumor immunity. Cell. 2017;169:1130–e11411111. 10.1016/j.cell.2017.05.005.28552348 10.1016/j.cell.2017.05.005
75. Lacher SM Bruttger J Kalt B Berthelet J Rajalingam K Wörtge S Waisman A HMG-CoA reductase promotes protein prenylation and therefore is indispensible for T-cell survival Cell Death Dis 2017 8 e2824 10.1038/cddis.2017.221 28542128
Lacher SM, Bruttger J, Kalt B, Berthelet J, Rajalingam K, Wörtge S, Waisman A. HMG-CoA reductase promotes protein prenylation and therefore is indispensible for T-cell survival. Cell Death Dis. 2017;8:e2824. 10.1038/cddis.2017.221.28542128 10.1038/cddis.2017.221
76. Toor SM Murshed K Al-Dhaheri M Khawar M Abu Nada M Elkord E Immune checkpoints in circulating and Tumor-infiltrating CD4(+) T cell subsets in Colorectal Cancer patients Front Immunol 2019 10 2936 10.3389/fimmu.2019.02936 31921188
Toor SM, Murshed K, Al-Dhaheri M, Khawar M, Abu Nada M, Elkord E. Immune checkpoints in circulating and Tumor-infiltrating CD4(+) T cell subsets in Colorectal Cancer patients. Front Immunol. 2019;10:2936. 10.3389/fimmu.2019.02936.31921188 10.3389/fimmu.2019.02936
77. Nakagawa H Sido JM Reyes EE Kiers V Cantor H Kim HJ Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity Proc Natl Acad Sci U S A 2016 113 6248 53 10.1073/pnas.1604765113 27185917
Nakagawa H, Sido JM, Reyes EE, Kiers V, Cantor H, Kim HJ. Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity. Proc Natl Acad Sci U S A. 2016;113:6248–53. 10.1073/pnas.1604765113.27185917 10.1073/pnas.1604765113
78. Kim HJ Barnitz RA Kreslavsky T Brown FD Moffett H Lemieux ME Kaygusuz Y Meissner T Holderried TA Chan S Stable inhibitory activity of regulatory T cells requires the transcription factor Helios Science 2015 350 334 9 10.1126/science.aad0616 26472910
Kim HJ, Barnitz RA, Kreslavsky T, Brown FD, Moffett H, Lemieux ME, Kaygusuz Y, Meissner T, Holderried TA, Chan S, et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science. 2015;350:334–9. 10.1126/science.aad0616.26472910 10.1126/science.aad0616
79. Pan F Yu H Dang EV Barbi J Pan X Grosso JF Jinasena D Sharma SM McCadden EM Getnet D Eos mediates Foxp3-dependent gene silencing in CD4 + regulatory T cells Science 2009 325 1142 6 10.1126/science.1176077 19696312
Pan F, Yu H, Dang EV, Barbi J, Pan X, Grosso JF, Jinasena D, Sharma SM, McCadden EM, Getnet D, et al. Eos mediates Foxp3-dependent gene silencing in CD4 + regulatory T cells. Science. 2009;325:1142–6. 10.1126/science.1176077.19696312 10.1126/science.1176077
80. Gokhale AS Gangaplara A Lopez-Occasio M Thornton AM Shevach EM Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity J Autoimmun 2019 105 102300 10.1016/j.jaut.2019.06.011 31296356
Gokhale AS, Gangaplara A, Lopez-Occasio M, Thornton AM, Shevach EM. Selective deletion of Eos (Ikzf4) in T-regulatory cells leads to loss of suppressive function and development of systemic autoimmunity. J Autoimmun. 2019;105:102300. 10.1016/j.jaut.2019.06.011.31296356 10.1016/j.jaut.2019.06.011
81. Hibino S Chikuma S Kondo T Ito M Nakatsukasa H Omata-Mise S Yoshimura A Inhibition of Nr4a receptors enhances Antitumor immunity by breaking Treg-mediated Immune Tolerance Cancer Res 2018 78 3027 40 10.1158/0008-5472.Can-17-3102 29559474
Hibino S, Chikuma S, Kondo T, Ito M, Nakatsukasa H, Omata-Mise S, Yoshimura A. Inhibition of Nr4a receptors enhances Antitumor immunity by breaking Treg-mediated Immune Tolerance. Cancer Res. 2018;78:3027–40. 10.1158/0008-5472.Can-17-3102.29559474 10.1158/0008-5472.Can-17-3102
82. Sharma S Yang SC Zhu L Reckamp K Gardner B Baratelli F Huang M Batra RK Dubinett SM Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4 + CD25 + T regulatory cell activities in lung cancer Cancer Res 2005 65 5211 20 10.1158/0008-5472.Can-05-0141 15958566
Sharma S, Yang SC, Zhu L, Reckamp K, Gardner B, Baratelli F, Huang M, Batra RK, Dubinett SM. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4 + CD25 + T regulatory cell activities in lung cancer. Cancer Res. 2005;65:5211–20. 10.1158/0008-5472.Can-05-0141.15958566 10.1158/0008-5472.Can-05-0141
83. Goswami S Apostolou I Zhang J Skepner J Anandhan S Zhang X Xiong L Trojer P Aparicio A Subudhi SK Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy J Clin Invest 2018 128 3813 8 10.1172/jci99760 29905573
Goswami S, Apostolou I, Zhang J, Skepner J, Anandhan S, Zhang X, Xiong L, Trojer P, Aparicio A, Subudhi SK, et al. Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J Clin Invest. 2018;128:3813–8. 10.1172/jci99760.29905573 10.1172/jci99760
84. Peng D Kryczek I Nagarsheth N Zhao L Wei S Wang W Sun Y Zhao E Vatan L Szeliga W Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy Nature 2015 527 249 53 10.1038/nature15520 26503055
Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, Sun Y, Zhao E, Vatan L, Szeliga W, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015;527:249–53. 10.1038/nature15520.26503055 10.1038/nature15520
85. Dangaj D Bruand M Grimm AJ Ronet C Barras D Duttagupta PA Lanitis E Duraiswamy J Tanyi JL Benencia F Cooperation between constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid tumors Cancer Cell 2019 35 885 e900810 10.1016/j.ccell.2019.05.004 31185212
Dangaj D, Bruand M, Grimm AJ, Ronet C, Barras D, Duttagupta PA, Lanitis E, Duraiswamy J, Tanyi JL, Benencia F, et al. Cooperation between constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid tumors. Cancer Cell. 2019;35:885–e900810. 10.1016/j.ccell.2019.05.004.31185212 10.1016/j.ccell.2019.05.004
86. Yin Y Qiu S Li X Huang B Xu Y Peng Y EZH2 suppression in glioblastoma shifts microglia toward M1 phenotype in tumor microenvironment J Neuroinflammation 2017 14 220 10.1186/s12974-017-0993-4 29132376
Yin Y, Qiu S, Li X, Huang B, Xu Y, Peng Y. EZH2 suppression in glioblastoma shifts microglia toward M1 phenotype in tumor microenvironment. J Neuroinflammation. 2017;14:220. 10.1186/s12974-017-0993-4.29132376 10.1186/s12974-017-0993-4
87. Karantanos T Chistofides A Barhdan K Li L Boussiotis VA Regulation of T cell differentiation and function by EZH2 Front Immunol 2016 7 172 10.3389/fimmu.2016.00172 27199994
Karantanos T, Chistofides A, Barhdan K, Li L, Boussiotis VA. Regulation of T cell differentiation and function by EZH2. Front Immunol. 2016;7:172. 10.3389/fimmu.2016.00172.27199994 10.3389/fimmu.2016.00172
88. Holt MP Punkosdy GA Glass DD Shevach EM TCR Signaling and CD28/CTLA-4 Signaling Cooperatively Modulate T Regulatory Cell Homeostasis J Immunol 2017 198 1503 11 10.4049/jimmunol.1601670 28053234
Holt MP, Punkosdy GA, Glass DD, Shevach EM. TCR Signaling and CD28/CTLA-4 Signaling Cooperatively Modulate T Regulatory Cell Homeostasis. J Immunol. 2017;198:1503–11. 10.4049/jimmunol.1601670.28053234 10.4049/jimmunol.1601670
89. Ephrem A Epstein AL Stephens GL Thornton AM Glass D Shevach EM Modulation of Treg cells/T effector function by GITR signaling is context-dependent Eur J Immunol 2013 43 2421 9 10.1002/eji.201343451 23722868
Ephrem A, Epstein AL, Stephens GL, Thornton AM, Glass D, Shevach EM. Modulation of Treg cells/T effector function by GITR signaling is context-dependent. Eur J Immunol. 2013;43:2421–9. 10.1002/eji.201343451.23722868 10.1002/eji.201343451
90. Plitas G Konopacki C Wu K Bos PD Morrow M Putintseva EV Chudakov DM Rudensky AY Regulatory T cells exhibit distinct features in human breast Cancer Immunity 2016 45 1122 34 10.1016/j.immuni.2016.10.032 27851913
Plitas G, Konopacki C, Wu K, Bos PD, Morrow M, Putintseva EV, Chudakov DM, Rudensky AY. Regulatory T cells exhibit distinct features in human breast Cancer. Immunity. 2016;45:1122–34. 10.1016/j.immuni.2016.10.032.27851913 10.1016/j.immuni.2016.10.032
91. Rech AJ Mick R Martin S Recio A Aqui NA Powell DJ Jr Colligon TA Trosko JA Leinbach LI Pletcher CH CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients Sci Transl Med 2012 4 134ra162 10.1126/scitranslmed.3003330
Rech AJ, Mick R, Martin S, Recio A, Aqui NA, Powell DJ Jr., Colligon TA, Trosko JA, Leinbach LI, Pletcher CH, et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci Transl Med. 2012;4:134ra162. 10.1126/scitranslmed.3003330.10.1126/scitranslmed.3003330
92. Feng Y Arvey A Chinen T van der Veeken J Gasteiger G Rudensky AY Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus Cell 2014 158 749 63 10.1016/j.cell.2014.07.031 25126783
Feng Y, Arvey A, Chinen T, van der Veeken J, Gasteiger G, Rudensky AY. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell. 2014;158:749–63. 10.1016/j.cell.2014.07.031.25126783 10.1016/j.cell.2014.07.031
93. Zhang R Huynh A Whitcher G Chang J Maltzman JS Turka LA An obligate cell-intrinsic function for CD28 in Tregs J Clin Invest 2013 123 580 93 10.1172/jci65013 23281398
Zhang R, Huynh A, Whitcher G, Chang J, Maltzman JS, Turka LA. An obligate cell-intrinsic function for CD28 in Tregs. J Clin Invest. 2013;123:580–93. 10.1172/jci65013.23281398 10.1172/jci65013
94. Vang KB Yang J Pagán AJ Li LX Wang J Green JM Beg AA Farrar MA Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development J Immunol 2010 184 4074 7 10.4049/jimmunol.0903933 20228198
Vang KB, Yang J, Pagán AJ, Li LX, Wang J, Green JM, Beg AA, Farrar MA. Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J Immunol. 2010;184:4074–7. 10.4049/jimmunol.0903933.20228198 10.4049/jimmunol.0903933
95. Marangoni F Zhang R Mani V Thelen M Ali Akbar NJ Warner RD Äijö T Zappulli V Martinez GJ Turka LA Tumor tolerance-promoting function of Regulatory T cells is optimized by CD28, but strictly dependent on Calcineurin J Immunol 2018 200 3647 61 10.4049/jimmunol.1701220 29661826
Marangoni F, Zhang R, Mani V, Thelen M, Ali Akbar NJ, Warner RD, Äijö T, Zappulli V, Martinez GJ, Turka LA, et al. Tumor tolerance-promoting function of Regulatory T cells is optimized by CD28, but strictly dependent on Calcineurin. J Immunol. 2018;200:3647–61. 10.4049/jimmunol.1701220.29661826 10.4049/jimmunol.1701220
96. Schaer DA Budhu S Liu C Bryson C Malandro N Cohen A Zhong H Yang X Houghton AN Merghoub T GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability Cancer Immunol Res 2013 1 320 31 10.1158/2326-6066.Cir-13-0086 24416730
Schaer DA, Budhu S, Liu C, Bryson C, Malandro N, Cohen A, Zhong H, Yang X, Houghton AN, Merghoub T, et al. GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. Cancer Immunol Res. 2013;1:320–31. 10.1158/2326-6066.Cir-13-0086.24416730 10.1158/2326-6066.Cir-13-0086
97. Cohen AD Schaer DA Liu C Li Y Hirschhorn-Cymmerman D Kim SC Diab A Rizzuto G Duan F Perales MA Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation PLoS ONE 2010 5 e10436 10.1371/journal.pone.0010436 20454651
Cohen AD, Schaer DA, Liu C, Li Y, Hirschhorn-Cymmerman D, Kim SC, Diab A, Rizzuto G, Duan F, Perales MA, et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS ONE. 2010;5:e10436. 10.1371/journal.pone.0010436.20454651 10.1371/journal.pone.0010436
98. Hansen W Hutzler M Abel S Alter C Stockmann C Kliche S Albert J Sparwasser T Sakaguchi S Westendorf AM Neuropilin 1 deficiency on CD4 + Foxp3 + regulatory T cells impairs mouse melanoma growth J Exp Med 2012 209 2001 16 10.1084/jem.20111497 23045606
Hansen W, Hutzler M, Abel S, Alter C, Stockmann C, Kliche S, Albert J, Sparwasser T, Sakaguchi S, Westendorf AM, et al. Neuropilin 1 deficiency on CD4 + Foxp3 + regulatory T cells impairs mouse melanoma growth. J Exp Med. 2012;209:2001–16. 10.1084/jem.20111497.23045606 10.1084/jem.20111497
99. Overacre-Delgoffe AE Vignali DAA Treg Fragility: a Prerequisite for Effective Antitumor Immunity? Cancer Immunol Res 2018 6 882 7 10.1158/2326-6066.Cir-18-0066 30068755
Overacre-Delgoffe AE, Vignali DAA. Treg Fragility: a Prerequisite for Effective Antitumor Immunity? Cancer Immunol Res. 2018;6:882–7. 10.1158/2326-6066.Cir-18-0066.30068755 10.1158/2326-6066.Cir-18-0066
100. Xu J Li X Yuan Q Wang C Xu L Wei X Liu H Yu B An Z Zhao Y The semaphorin 4A-neuropilin 1 axis alleviates kidney ischemia reperfusion injury by promoting the stability and function of regulatory T cells Kidney Int 2021 100 1268 81 10.1016/j.kint.2021.08.023 34534552
Xu J, Li X, Yuan Q, Wang C, Xu L, Wei X, Liu H, Yu B, An Z, Zhao Y, et al. The semaphorin 4A-neuropilin 1 axis alleviates kidney ischemia reperfusion injury by promoting the stability and function of regulatory T cells. Kidney Int. 2021;100:1268–81. 10.1016/j.kint.2021.08.023.34534552 10.1016/j.kint.2021.08.023
101. Hahn YS Ji XY Woo SI Choi YK Song MS Shin KS Jin N O’Brien RL Born WK Vγ1 + γδ T cells reduce IL-10-producing CD4 + CD25 + T cells in the lung of ovalbumin-sensitized and challenged mice Immunol Lett 2008 121 87 92 10.1016/j.imlet.2008.09.001 18840468
Hahn YS, Ji XY, Woo SI, Choi YK, Song MS, Shin KS, Jin N, O’Brien RL, Born WK. Vγ1 + γδ T cells reduce IL-10-producing CD4 + CD25 + T cells in the lung of ovalbumin-sensitized and challenged mice. Immunol Lett. 2008;121:87–92. 10.1016/j.imlet.2008.09.001.18840468 10.1016/j.imlet.2008.09.001
102. Bianchi E Doe B Goulding D Wright GJ Juno is the egg izumo receptor and is essential for mammalian fertilization Nature 2014 508 483 7 10.1038/nature13203 24739963
Bianchi E, Doe B, Goulding D, Wright GJ. Juno is the egg izumo receptor and is essential for mammalian fertilization. Nature. 2014;508:483–7. 10.1038/nature13203.24739963 10.1038/nature13203
103. Zarin P Shwartz Y Ortiz-Lopez A Hanna BS Sassone-Corsi M Hsu YC Mathis D Benoist C Treg cells require Izumo1R to regulate γδT cell-driven inflammation in the skin Proc Natl Acad Sci U S A 2023 120 e2221255120 10.1073/pnas.2221255120 36972453
Zarin P, Shwartz Y, Ortiz-Lopez A, Hanna BS, Sassone-Corsi M, Hsu YC, Mathis D, Benoist C. Treg cells require Izumo1R to regulate γδT cell-driven inflammation in the skin. Proc Natl Acad Sci U S A. 2023;120:e2221255120. 10.1073/pnas.2221255120.36972453 10.1073/pnas.2221255120
104. Alfar R Napoleon JV Shahriar I Finnell R Walchle C Johnson A Low PS Selective reprogramming of regulatory T cells in solid tumors can strongly enhance or inhibit tumor growth Front Immunol 2023 14 1274199 10.3389/fimmu.2023.1274199 37928524
Alfar R, Napoleon JV, Shahriar I, Finnell R, Walchle C, Johnson A, Low PS. Selective reprogramming of regulatory T cells in solid tumors can strongly enhance or inhibit tumor growth. Front Immunol. 2023;14:1274199. 10.3389/fimmu.2023.1274199.37928524 10.3389/fimmu.2023.1274199
105. Kim MJ Kim K Park HJ Kim GR Hong KH Oh JH Son J Park DJ Kim D Choi JM Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells Nat Immunol 2023 24 148 61 10.1038/s41590-022-01373-1 36577929
Kim MJ, Kim K, Park HJ, Kim GR, Hong KH, Oh JH, Son J, Park DJ, Kim D, Choi JM, et al. Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells. Nat Immunol. 2023;24:148–61. 10.1038/s41590-022-01373-1.36577929 10.1038/s41590-022-01373-1
106. Wang Z Wu X Study and analysis of antitumor resistance mechanism of PD1/PD-L1 immune checkpoint blocker Cancer Med 2020 9 8086 121 10.1002/cam4.3410 32875727
Wang Z, Wu X. Study and analysis of antitumor resistance mechanism of PD1/PD-L1 immune checkpoint blocker. Cancer Med. 2020;9:8086–121. 10.1002/cam4.3410.32875727 10.1002/cam4.3410
107. Pang K Shi ZD Wei LY Dong Y Ma YY Wang W Wang GY Cao MY Dong JJ Chen YA Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1/PD-L1 blockade Drug Resist Updat 2023 66 100907 10.1016/j.drup.2022.100907 36527888
Pang K, Shi ZD, Wei LY, Dong Y, Ma YY, Wang W, Wang GY, Cao MY, Dong JJ, Chen YA, et al. Research progress of therapeutic effects and drug resistance of immunotherapy based on PD-1/PD-L1 blockade. Drug Resist Updat. 2023;66:100907. 10.1016/j.drup.2022.100907.36527888 10.1016/j.drup.2022.100907
108. Kamada T Togashi Y Tay C Ha D Sasaki A Nakamura Y Sato E Fukuoka S Tada Y Tanaka A PD-1(+) regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer Proc Natl Acad Sci U S A 2019 116 9999 10008 10.1073/pnas.1822001116 31028147
Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, Sato E, Fukuoka S, Tada Y, Tanaka A, et al. PD-1(+) regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci U S A. 2019;116:9999–10008. 10.1073/pnas.1822001116.31028147 10.1073/pnas.1822001116
109. Ferrara R Mezquita L Texier M Lahmar J Audigier-Valette C Tessonnier L Mazieres J Zalcman G Brosseau S Le Moulec S Hyperprogressive Disease in patients with Advanced Non-small Cell Lung Cancer treated with PD-1/PD-L1 inhibitors or with single-Agent Chemotherapy JAMA Oncol 2018 4 1543 52 10.1001/jamaoncol.2018.3676 30193240
Ferrara R, Mezquita L, Texier M, Lahmar J, Audigier-Valette C, Tessonnier L, Mazieres J, Zalcman G, Brosseau S, Le Moulec S, et al. Hyperprogressive Disease in patients with Advanced Non-small Cell Lung Cancer treated with PD-1/PD-L1 inhibitors or with single-Agent Chemotherapy. JAMA Oncol. 2018;4:1543–52. 10.1001/jamaoncol.2018.3676.30193240 10.1001/jamaoncol.2018.3676
110. Kim KH Hur JY Koh J Cho J Ku BM Koh JY Sun JM Lee SH Ahn JS Park K Immunological characteristics of Hyperprogressive Disease in patients with non-small cell Lung Cancer treated with Anti-PD-1/PD-L1 abs Immune Netw 2020 20 e48 10.4110/in.2020.20.e48 33425433
Kim KH, Hur JY, Koh J, Cho J, Ku BM, Koh JY, Sun JM, Lee SH, Ahn JS, Park K, et al. Immunological characteristics of Hyperprogressive Disease in patients with non-small cell Lung Cancer treated with Anti-PD-1/PD-L1 abs. Immune Netw. 2020;20:e48. 10.4110/in.2020.20.e48.33425433 10.4110/in.2020.20.e48
111. Buchbinder EI Desai A CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition Am J Clin Oncol 2016 39 98 106 10.1097/coc.0000000000000239 26558876
Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39:98–106. 10.1097/coc.0000000000000239.26558876 10.1097/coc.0000000000000239
112. Sasidharan Nair V Elkord E Immune checkpoint inhibitors in cancer therapy: a focus on T-regulatory cells Immunol Cell Biol 2018 96 21 33 10.1111/imcb.1003 29359507
Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors in cancer therapy: a focus on T-regulatory cells. Immunol Cell Biol. 2018;96:21–33. 10.1111/imcb.1003.29359507 10.1111/imcb.1003
113. Arce Vargas F Furness AJS Litchfield K Joshi K Rosenthal R Ghorani E Solomon I Lesko MH Ruef N Roddie C Fc effector function contributes to the activity of human Anti-CTLA-4 antibodies Cancer Cell 2018 33 649 e663644 10.1016/j.ccell.2018.02.010 29576375
Arce Vargas F, Furness AJS, Litchfield K, Joshi K, Rosenthal R, Ghorani E, Solomon I, Lesko MH, Ruef N, Roddie C, et al. Fc effector function contributes to the activity of human Anti-CTLA-4 antibodies. Cancer Cell. 2018;33:649–e663644. 10.1016/j.ccell.2018.02.010.29576375 10.1016/j.ccell.2018.02.010
114. Harjunpää H Guillerey C TIGIT as an emerging immune checkpoint Clin Exp Immunol 2020 200 108 19 10.1111/cei.13407 31828774
Harjunpää H, Guillerey C. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 2020;200:108–19. 10.1111/cei.13407.31828774 10.1111/cei.13407
115. Kojima M Suzuki K Takeshita M Ohyagi M Iizuka M Yamane H Koga K Kouro T Kassai Y Yoshihara T Anti-human-TIGIT agonistic antibody ameliorates autoimmune diseases by inhibiting tfh and tph cells and enhancing Treg cells Commun Biol 2023 6 500 10.1038/s42003-023-04874-3 37161050
Kojima M, Suzuki K, Takeshita M, Ohyagi M, Iizuka M, Yamane H, Koga K, Kouro T, Kassai Y, Yoshihara T, et al. Anti-human-TIGIT agonistic antibody ameliorates autoimmune diseases by inhibiting tfh and tph cells and enhancing Treg cells. Commun Biol. 2023;6:500. 10.1038/s42003-023-04874-3.37161050 10.1038/s42003-023-04874-3
116. Guan X Hu R Choi Y Srivats S Nabet BY Silva J McGinnis L Hendricks R Nutsch K Banta KL Anti-TIGIT antibody improves PD-L1 blockade through myeloid and T(reg) cells Nature 2024 627 646 55 10.1038/s41586-024-07121-9 38418879
Guan X, Hu R, Choi Y, Srivats S, Nabet BY, Silva J, McGinnis L, Hendricks R, Nutsch K, Banta KL, et al. Anti-TIGIT antibody improves PD-L1 blockade through myeloid and T(reg) cells. Nature. 2024;627:646–55. 10.1038/s41586-024-07121-9.38418879 10.1038/s41586-024-07121-9
117. Yang X Yan Y Wang F Tian J Cao Q Liu M Ma B Su C Duan X Aspirin prevents colorectal cancer by regulating the abundance of Enterococcus cecorum and TIGIT(+)Treg cells Sci Rep 2024 14 13592 10.1038/s41598-024-64447-0 38867002
Yang X, Yan Y, Wang F, Tian J, Cao Q, Liu M, Ma B, Su C, Duan X. Aspirin prevents colorectal cancer by regulating the abundance of Enterococcus cecorum and TIGIT(+)Treg cells. Sci Rep. 2024;14:13592. 10.1038/s41598-024-64447-0.38867002 10.1038/s41598-024-64447-0
118. Campbell DJ Koch MA Phenotypical and functional specialization of FOXP3 + regulatory T cells Nat Rev Immunol 2011 11 119 30 10.1038/nri2916 21267013
Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3 + regulatory T cells. Nat Rev Immunol. 2011;11:119–30. 10.1038/nri2916.21267013 10.1038/nri2916
119. Halim L Romano M McGregor R Correa I Pavlidis P Grageda N Hoong SJ Yuksel M Jassem W Hannen RF An Atlas of Human Regulatory T Helper-Like Cells Reveals Features of Th2-like Tregs that support a tumorigenic environment Cell Rep 2017 20 757 70 10.1016/j.celrep.2017.06.079 28723576
Halim L, Romano M, McGregor R, Correa I, Pavlidis P, Grageda N, Hoong SJ, Yuksel M, Jassem W, Hannen RF, et al. An Atlas of Human Regulatory T Helper-Like Cells Reveals Features of Th2-like Tregs that support a tumorigenic environment. Cell Rep. 2017;20:757–70. 10.1016/j.celrep.2017.06.079.28723576 10.1016/j.celrep.2017.06.079
120. Roider HG Hoff S Tseng SY Berndt S Trautwein M Filarsky K Gritzan U Camps J Nadler WM Grudzinska-Goebel J Selective depletion of tumor-infiltrating regulatory T cells with BAY 3375968, a novel Fc-optimized anti-CCR8 antibody Clin Exp Med 2024 24 122 10.1007/s10238-024-01362-8 38856863
Roider HG, Hoff S, Tseng SY, Berndt S, Trautwein M, Filarsky K, Gritzan U, Camps J, Nadler WM, Grudzinska-Goebel J, et al. Selective depletion of tumor-infiltrating regulatory T cells with BAY 3375968, a novel Fc-optimized anti-CCR8 antibody. Clin Exp Med. 2024;24:122. 10.1007/s10238-024-01362-8.38856863 10.1007/s10238-024-01362-8
121. Marshall LA, Marubayashi S, Jorapur A, Jacobson S, Zibinsky M, Robles O, Hu DX, Jackson JJ, Pookot D, Sanchez J, et al. Tumors establish resistance to immunotherapy by regulating T(reg) recruitment via CCR4. J Immunother Cancer. 2020;8. 10.1136/jitc-2020-000764.
122. Qian BZ Pollard JW Macrophage diversity enhances tumor progression and metastasis Cell 2010 141 39 51 10.1016/j.cell.2010.03.014 20371344
Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141:39–51. 10.1016/j.cell.2010.03.014.20371344 10.1016/j.cell.2010.03.014
123. Chiu DK Xu IM Lai RK Tse AP Wei LL Koh HY Li LL Lee D Lo RC Wong CM Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26 Hepatology 2016 64 797 813 10.1002/hep.28655 27228567
Chiu DK, Xu IM, Lai RK, Tse AP, Wei LL, Koh HY, Li LL, Lee D, Lo RC, Wong CM, et al. Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26. Hepatology. 2016;64:797–813. 10.1002/hep.28655.27228567 10.1002/hep.28655
124. De Simone M Arrigoni A Rossetti G Gruarin P Ranzani V Politano C Bonnal RJP Provasi E Sarnicola ML Panzeri I Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells Immunity 2016 45 1135 47 10.1016/j.immuni.2016.10.021 27851914
De Simone M, Arrigoni A, Rossetti G, Gruarin P, Ranzani V, Politano C, Bonnal RJP, Provasi E, Sarnicola ML, Panzeri I, et al. Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells. Immunity. 2016;45:1135–47. 10.1016/j.immuni.2016.10.021.27851914 10.1016/j.immuni.2016.10.021
125. Redjimi N Raffin C Raimbaud I Pignon P Matsuzaki J Odunsi K Valmori D Ayyoub M CXCR3 + T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity Cancer Res 2012 72 4351 60 10.1158/0008-5472.Can-12-0579 22798340
Redjimi N, Raffin C, Raimbaud I, Pignon P, Matsuzaki J, Odunsi K, Valmori D, Ayyoub M. CXCR3 + T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Res. 2012;72:4351–60. 10.1158/0008-5472.Can-12-0579.22798340 10.1158/0008-5472.Can-12-0579
126. Keerthivasan S Aghajani K Dose M Molinero L Khan MW Venkateswaran V Weber C Emmanuel AO Sun T Bentrem DJ β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells Sci Transl Med 2014 6 225ra228 10.1126/scitranslmed.3007607
Keerthivasan S, Aghajani K, Dose M, Molinero L, Khan MW, Venkateswaran V, Weber C, Emmanuel AO, Sun T, Bentrem DJ, et al. β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells. Sci Transl Med. 2014;6:225ra228. 10.1126/scitranslmed.3007607.10.1126/scitranslmed.3007607
127. Rosenbaum M Gewies A Pechloff K Heuser C Engleitner T Gehring T Hartjes L Krebs S Krappmann D Kriegsmann M Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells Nat Commun 2019 10 2352 10.1038/s41467-019-10203-2 31138793
Rosenbaum M, Gewies A, Pechloff K, Heuser C, Engleitner T, Gehring T, Hartjes L, Krebs S, Krappmann D, Kriegsmann M, et al. Bcl10-controlled Malt1 paracaspase activity is key for the immune suppressive function of regulatory T cells. Nat Commun. 2019;10:2352. 10.1038/s41467-019-10203-2.31138793 10.1038/s41467-019-10203-2
128. DeVore SB Khurana Hershey GK The role of the CBM complex in allergic inflammation and disease J Allergy Clin Immunol 2022 150 1011 30 10.1016/j.jaci.2022.06.023 35981904
DeVore SB, Khurana Hershey GK. The role of the CBM complex in allergic inflammation and disease. J Allergy Clin Immunol. 2022;150:1011–30. 10.1016/j.jaci.2022.06.023.35981904 10.1016/j.jaci.2022.06.023
129. Brüstle A Brenner D Knobbe-Thomsen CB Cox M Lang PA Lang KS Mak TW MALT1 is an intrinsic regulator of regulatory T cells Cell Death Differ 2017 24 1214 23 10.1038/cdd.2015.104 26405015
Brüstle A, Brenner D, Knobbe-Thomsen CB, Cox M, Lang PA, Lang KS, Mak TW. MALT1 is an intrinsic regulator of regulatory T cells. Cell Death Differ. 2017;24:1214–23. 10.1038/cdd.2015.104.26405015 10.1038/cdd.2015.104
130. Long M Park SG Strickland I Hayden MS Ghosh S Nuclear factor-kappab modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor Immunity 2009 31 921 31 10.1016/j.immuni.2009.09.022 20064449
Long M, Park SG, Strickland I, Hayden MS, Ghosh S. Nuclear factor-kappab modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity. 2009;31:921–31. 10.1016/j.immuni.2009.09.022.20064449 10.1016/j.immuni.2009.09.022
131. Yu J Zhou X Chang M Nakaya M Chang JH Xiao Y Lindsey JW Dorta-Estremera S Cao W Zal A Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation Nat Commun 2015 6 6074 10.1038/ncomms7074 25606824
Yu J, Zhou X, Chang M, Nakaya M, Chang JH, Xiao Y, Lindsey JW, Dorta-Estremera S, Cao W, Zal A, et al. Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation. Nat Commun. 2015;6:6074. 10.1038/ncomms7074.25606824 10.1038/ncomms7074
132. Xia M David L Teater M Gutierrez J Wang X Meydan C Lytle A Slack GW Scott DW Morin RD BCL10 mutations define distinct dependencies guiding Precision Therapy for DLBCL Cancer Discov 2022 12 1922 41 10.1158/2159-8290.Cd-21-1566 35658124
Xia M, David L, Teater M, Gutierrez J, Wang X, Meydan C, Lytle A, Slack GW, Scott DW, Morin RD, et al. BCL10 mutations define distinct dependencies guiding Precision Therapy for DLBCL. Cancer Discov. 2022;12:1922–41. 10.1158/2159-8290.Cd-21-1566.35658124 10.1158/2159-8290.Cd-21-1566
133. O’Neill TJ Gewies A Seeholzer T Krappmann D TRAF6 controls T cell homeostasis by maintaining the equilibrium of MALT1 scaffolding and protease functions Front Immunol 2023 14 1111398 10.3389/fimmu.2023.1111398 36761777
O’Neill TJ, Gewies A, Seeholzer T, Krappmann D. TRAF6 controls T cell homeostasis by maintaining the equilibrium of MALT1 scaffolding and protease functions. Front Immunol. 2023;14:1111398. 10.3389/fimmu.2023.1111398.36761777 10.3389/fimmu.2023.1111398
134. Di Pilato M Gao Y Sun Y Fu A Grass C Seeholzer T Feederle R Mazo I Kazer SW Litchfield K Translational studies using the MALT1 inhibitor (S)-Mepazine to Induce Treg Fragility and Potentiate Immune Checkpoint Therapy in Cancer J Immunother Precis Oncol 2023 6 61 73 10.36401/jipo-22-18 37214210
Di Pilato M, Gao Y, Sun Y, Fu A, Grass C, Seeholzer T, Feederle R, Mazo I, Kazer SW, Litchfield K, et al. Translational studies using the MALT1 inhibitor (S)-Mepazine to Induce Treg Fragility and Potentiate Immune Checkpoint Therapy in Cancer. J Immunother Precis Oncol. 2023;6:61–73. 10.36401/jipo-22-18.37214210 10.36401/jipo-22-18
135. Mempel TR, Krappmann D. Combining precision oncology and immunotherapy by targeting the MALT1 protease. J Immunother Cancer. 2022;10. 10.1136/jitc-2022-005442.
136. Fujiwara M, Raheja R, Garo LP, Ajay AK, Kadowaki-Saga R, Karandikar SH, Gabriely G, Krishnan R, Beynon V, Paul A, et al. microRNA-92a promotes CNS autoimmunity by modulating the regulatory and inflammatory T cell balance. J Clin Invest. 2022;132. 10.1172/jci155693.
137. Saliminejad K Khorram Khorshid HR Soleymani Fard S Ghaffari SH An overview of microRNAs: Biology, functions, therapeutics, and analysis methods J Cell Physiol 2019 234 5451 65 10.1002/jcp.27486 30471116
Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol. 2019;234:5451–65. 10.1002/jcp.27486.30471116 10.1002/jcp.27486
138. Gangemi CMA Alaimo S Pulvirenti A García-Viñuales S Milardi D Falanga AP Fragalà ME Oliviero G Piccialli G Borbone N Endogenous and artificial miRNAs explore a rich variety of conformations: a potential relationship between secondary structure and biological functionality Sci Rep 2020 10 453 10.1038/s41598-019-57289-8 31949213
Gangemi CMA, Alaimo S, Pulvirenti A, García-Viñuales S, Milardi D, Falanga AP, Fragalà ME, Oliviero G, Piccialli G, Borbone N, et al. Endogenous and artificial miRNAs explore a rich variety of conformations: a potential relationship between secondary structure and biological functionality. Sci Rep. 2020;10:453. 10.1038/s41598-019-57289-8.31949213 10.1038/s41598-019-57289-8
139. Marson A Kretschmer K Frampton GM Jacobsen ES Polansky JK MacIsaac KD Levine SS Fraenkel E von Boehmer H Young RA Foxp3 occupancy and regulation of key target genes during T-cell stimulation Nature 2007 445 931 5 10.1038/nature05478 17237765
Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD, Levine SS, Fraenkel E, von Boehmer H, Young RA. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature. 2007;445:931–5. 10.1038/nature05478.17237765 10.1038/nature05478
140. Sadlon TJ Wilkinson BG Pederson S Brown CY Bresatz S Gargett T Melville EL Peng K D’Andrea RJ Glonek GG Genome-wide identification of human FOXP3 target genes in natural regulatory T cells J Immunol 2010 185 1071 81 10.4049/jimmunol.1000082 20554955
Sadlon TJ, Wilkinson BG, Pederson S, Brown CY, Bresatz S, Gargett T, Melville EL, Peng K, D’Andrea RJ, Glonek GG, et al. Genome-wide identification of human FOXP3 target genes in natural regulatory T cells. J Immunol. 2010;185:1071–81. 10.4049/jimmunol.1000082.20554955 10.4049/jimmunol.1000082
141. Beyer M Thabet Y Müller RU Sadlon T Classen S Lahl K Basu S Zhou X Bailey-Bucktrout SL Krebs W Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation Nat Immunol 2011 12 898 907 10.1038/ni.2084 21841785
Beyer M, Thabet Y, Müller RU, Sadlon T, Classen S, Lahl K, Basu S, Zhou X, Bailey-Bucktrout SL, Krebs W, et al. Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nat Immunol. 2011;12:898–907. 10.1038/ni.2084.21841785 10.1038/ni.2084
142. Ouyang W Liao W Luo CT Yin N Huse M Kim MV Peng M Chan P Ma Q Mo Y Novel Foxo1-dependent transcriptional programs control T(reg) cell function Nature 2012 491 554 9 10.1038/nature11581 23135404
Ouyang W, Liao W, Luo CT, Yin N, Huse M, Kim MV, Peng M, Chan P, Ma Q, Mo Y, et al. Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature. 2012;491:554–9. 10.1038/nature11581.23135404 10.1038/nature11581
143. Rani M Kumari R Singh SP Devi A Bansal P Siddiqi A Alsahli MA Almatroodi SA Rahmani AH Rizvi MMA MicroRNAs as master regulators of FOXO transcription factors in cancer management Life Sci 2023 321 121535 10.1016/j.lfs.2023.121535 36906255
Rani M, Kumari R, Singh SP, Devi A, Bansal P, Siddiqi A, Alsahli MA, Almatroodi SA, Rahmani AH, Rizvi MMA. MicroRNAs as master regulators of FOXO transcription factors in cancer management. Life Sci. 2023;321:121535. 10.1016/j.lfs.2023.121535.36906255 10.1016/j.lfs.2023.121535
144. Wang J, Wang Q, Guan Y, Sun Y, Wang X, Lively K, Wang Y, Luo M, Kim JA, Murphy EA, et al. Breast cancer cell-derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and antitumor function. J Clin Invest. 2022;132. 10.1172/jci157248.
145. Xue M Zhang X Chen J Liu F Xu J Xie J Yang Y Yu W Qiu H Mesenchymal stem cell-secreted TGF-β1 restores Treg/Th17 Skewing Induced by Lipopolysaccharide and Hypoxia Challenge via miR-155 suppression Stem Cells Int 2022 2022 5522828 10.1155/2022/5522828 35313652
Xue M, Zhang X, Chen J, Liu F, Xu J, Xie J, Yang Y, Yu W, Qiu H. Mesenchymal stem cell-secreted TGF-β1 restores Treg/Th17 Skewing Induced by Lipopolysaccharide and Hypoxia Challenge via miR-155 suppression. Stem Cells Int. 2022;2022:5522828. 10.1155/2022/5522828.35313652 10.1155/2022/5522828
146. Kohlhaas S Garden OA Scudamore C Turner M Okkenhaug K Vigorito E Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells J Immunol 2009 182 2578 82 10.4049/jimmunol.0803162 19234151
Kohlhaas S, Garden OA, Scudamore C, Turner M, Okkenhaug K, Vigorito E. Cutting edge: the Foxp3 target miR-155 contributes to the development of regulatory T cells. J Immunol. 2009;182:2578–82. 10.4049/jimmunol.0803162.19234151 10.4049/jimmunol.0803162
147. Wang WL Ouyang C Graham NM Zhang Y Cassady K Reyes EY Xiong M Davis AM Tang K Zeng D microRNA-142 guards against autoimmunity by controlling Treg cell homeostasis and function PLoS Biol 2022 20 e3001552 10.1371/journal.pbio.3001552 35180231
Wang WL, Ouyang C, Graham NM, Zhang Y, Cassady K, Reyes EY, Xiong M, Davis AM, Tang K, Zeng D, et al. microRNA-142 guards against autoimmunity by controlling Treg cell homeostasis and function. PLoS Biol. 2022;20:e3001552. 10.1371/journal.pbio.3001552.35180231 10.1371/journal.pbio.3001552
148. Łyszkiewicz M Winter SJ Witzlau K Föhse L Brownlie R Puchałka J Verheyden NA Kunze-Schumacher H Imelmann E Blume J miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity PLoS Biol 2019 17 e2006716 10.1371/journal.pbio.2006716 30856173
Łyszkiewicz M, Winter SJ, Witzlau K, Föhse L, Brownlie R, Puchałka J, Verheyden NA, Kunze-Schumacher H, Imelmann E, Blume J, et al. miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity. PLoS Biol. 2019;17:e2006716. 10.1371/journal.pbio.2006716.30856173 10.1371/journal.pbio.2006716
149. Jiang S Li C Olive V Lykken E Feng F Sevilla J Wan Y He L Li QJ Molecular dissection of the mir-17-92 cluster’s critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation Blood 2011 118 5487 97 10.1182/blood-2011-05-355644 21972292
Jiang S, Li C, Olive V, Lykken E, Feng F, Sevilla J, Wan Y, He L, Li QJ. Molecular dissection of the mir-17-92 cluster’s critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation. Blood. 2011;118:5487–97. 10.1182/blood-2011-05-355644.21972292 10.1182/blood-2011-05-355644
150. Rouas R Fayyad-Kazan H El Zein N Lewalle P Rothé F Simion A Akl H Mourtada M El Rifai M Burny A Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression Eur J Immunol 2009 39 1608 18 10.1002/eji.200838509 19408243
Rouas R, Fayyad-Kazan H, El Zein N, Lewalle P, Rothé F, Simion A, Akl H, Mourtada M, El Rifai M, Burny A, et al. Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol. 2009;39:1608–18. 10.1002/eji.200838509.19408243 10.1002/eji.200838509
151. Lu LF Boldin MP Chaudhry A Lin LL Taganov KD Hanada T Yoshimura A Baltimore D Rudensky AY Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses Cell 2010 142 914 29 10.1016/j.cell.2010.08.012 20850013
Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, Hanada T, Yoshimura A, Baltimore D, Rudensky AY. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell. 2010;142:914–29. 10.1016/j.cell.2010.08.012.20850013 10.1016/j.cell.2010.08.012
152. Sadlon T Brown CY Bandara V Hope CM Schjenken JE Pederson SM Breen J Forrest A Beyer M Robertson S Unravelling the molecular basis for regulatory T-cell plasticity and loss of function in disease Clin Transl Immunol 2018 7 e1011 10.1002/cti2.1011
Sadlon T, Brown CY, Bandara V, Hope CM, Schjenken JE, Pederson SM, Breen J, Forrest A, Beyer M, Robertson S, et al. Unravelling the molecular basis for regulatory T-cell plasticity and loss of function in disease. Clin Transl Immunol. 2018;7:e1011. 10.1002/cti2.1011.10.1002/cti2.1011
153. Zeng Q Liu W Luo R Lu G MicroRNA-181a and microRNA-155 are involved in the regulation of the differentiation and function of regulatory T cells in allergic rhinitis children Pediatr Allergy Immunol 2019 30 434 42 10.1111/pai.13038 30734973
Zeng Q, Liu W, Luo R, Lu G. MicroRNA-181a and microRNA-155 are involved in the regulation of the differentiation and function of regulatory T cells in allergic rhinitis children. Pediatr Allergy Immunol. 2019;30:434–42. 10.1111/pai.13038.30734973 10.1111/pai.13038
154. Serr I, Scherm MG, Zahm AM, Schug J, Flynn VK, Hippich M, Kälin S, Becker M, Achenbach P, Nikolaev A, et al. A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. Sci Transl Med. 2018;10. 10.1126/scitranslmed.aag1782.
155. Lin C Yang L Long noncoding RNA in Cancer: Wiring Signaling Circuitry Trends Cell Biol 2018 28 287 301 10.1016/j.tcb.2017.11.008 29274663
Lin C, Yang L. Long noncoding RNA in Cancer: Wiring Signaling Circuitry. Trends Cell Biol. 2018;28:287–301. 10.1016/j.tcb.2017.11.008.29274663 10.1016/j.tcb.2017.11.008
156. Qiao YQ Huang ML Xu AT Zhao D Ran ZH Shen J LncRNA DQ786243 affects Treg related CREB and Foxp3 expression in Crohn’s disease J Biomed Sci 2013 20 87 10.1186/1423-0127-20-87 24289115
Qiao YQ, Huang ML, Xu AT, Zhao D, Ran ZH, Shen J. LncRNA DQ786243 affects Treg related CREB and Foxp3 expression in Crohn’s disease. J Biomed Sci. 2013;20:87. 10.1186/1423-0127-20-87.24289115 10.1186/1423-0127-20-87
157. Zemmour D Pratama A Loughhead SM Mathis D Benoist C Flicr, a long noncoding RNA, modulates Foxp3 expression and autoimmunity Proc Natl Acad Sci U S A 2017 114 E3472 80 10.1073/pnas.1700946114 28396406
Zemmour D, Pratama A, Loughhead SM, Mathis D, Benoist C. Flicr, a long noncoding RNA, modulates Foxp3 expression and autoimmunity. Proc Natl Acad Sci U S A. 2017;114:E3472–80. 10.1073/pnas.1700946114.28396406 10.1073/pnas.1700946114
158. Dong L Zhou S Bai X He X Construction of a prognostic model for HCC based on ferroptosis-related lncRNAs expression and its potential to predict the response and irAEs of immunotherapy Front Pharmacol 2023 14 1090895 10.3389/fphar.2023.1090895 36992841
Dong L, Zhou S, Bai X, He X. Construction of a prognostic model for HCC based on ferroptosis-related lncRNAs expression and its potential to predict the response and irAEs of immunotherapy. Front Pharmacol. 2023;14:1090895. 10.3389/fphar.2023.1090895.36992841 10.3389/fphar.2023.1090895
159. Brunner SM Schiechl G Falk W Schlitt HJ Geissler EK Fichtner-Feigl S Interleukin-33 prolongs allograft survival during chronic cardiac rejection Transpl Int 2011 24 1027 39 10.1111/j.1432-2277.2011.01306.x 21797940
Brunner SM, Schiechl G, Falk W, Schlitt HJ, Geissler EK, Fichtner-Feigl S. Interleukin-33 prolongs allograft survival during chronic cardiac rejection. Transpl Int. 2011;24:1027–39. 10.1111/j.1432-2277.2011.01306.x.21797940 10.1111/j.1432-2277.2011.01306.x
160. Griesenauer B Jiang H Yang J Zhang J Ramadan AM Egbosiuba J Campa K Paczesny S ST2/MyD88 Deficiency protects mice against Acute Graft-versus-Host Disease and Spares Regulatory T Cells J Immunol 2019 202 3053 64 10.4049/jimmunol.1800447 30979817
Griesenauer B, Jiang H, Yang J, Zhang J, Ramadan AM, Egbosiuba J, Campa K, Paczesny S. ST2/MyD88 Deficiency protects mice against Acute Graft-versus-Host Disease and Spares Regulatory T Cells. J Immunol. 2019;202:3053–64. 10.4049/jimmunol.1800447.30979817 10.4049/jimmunol.1800447
161. Hatzioannou A Banos A Sakelaropoulos T Fedonidis C Vidali MS Köhne M Händler K Boon L Henriques A Koliaraki V An intrinsic role of IL-33 in T(reg) cell-mediated tumor immunoevasion Nat Immunol 2020 21 75 85 10.1038/s41590-019-0555-2 31844326
Hatzioannou A, Banos A, Sakelaropoulos T, Fedonidis C, Vidali MS, Köhne M, Händler K, Boon L, Henriques A, Koliaraki V, et al. An intrinsic role of IL-33 in T(reg) cell-mediated tumor immunoevasion. Nat Immunol. 2020;21:75–85. 10.1038/s41590-019-0555-2.31844326 10.1038/s41590-019-0555-2
162. Smithgall MD Comeau MR Yoon BR Kaufman D Armitage R Smith DE IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells Int Immunol 2008 20 1019 30 10.1093/intimm/dxn060 18550585
Smithgall MD, Comeau MR, Yoon BR, Kaufman D, Armitage R, Smith DE. IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int Immunol. 2008;20:1019–30. 10.1093/intimm/dxn060.18550585 10.1093/intimm/dxn060
163. Sharma MD Huang L Choi JH Lee EJ Wilson JM Lemos H Pan F Blazar BR Pardoll DM Mellor AL An inherently bifunctional subset of Foxp3 + T helper cells is controlled by the transcription factor eos Immunity 2013 38 998 1012 10.1016/j.immuni.2013.01.013 23684987
Sharma MD, Huang L, Choi JH, Lee EJ, Wilson JM, Lemos H, Pan F, Blazar BR, Pardoll DM, Mellor AL, et al. An inherently bifunctional subset of Foxp3 + T helper cells is controlled by the transcription factor eos. Immunity. 2013;38:998–1012. 10.1016/j.immuni.2013.01.013.23684987 10.1016/j.immuni.2013.01.013
164. Sharma MD Shinde R McGaha TL Huang L Holmgaard RB Wolchok JD Mautino MR Celis E Sharpe AH Francisco LM The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment Sci Adv 2015 1 e1500845 10.1126/sciadv.1500845 26601142
Sharma MD, Shinde R, McGaha TL, Huang L, Holmgaard RB, Wolchok JD, Mautino MR, Celis E, Sharpe AH, Francisco LM, et al. The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Sci Adv. 2015;1:e1500845. 10.1126/sciadv.1500845.26601142 10.1126/sciadv.1500845
165. Hsieh WC Hsu TS Chang YJ Lai MZ IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells Nat Commun 2018 9 463 10.1038/s41467-018-02862-4 29386580
Hsieh WC, Hsu TS, Chang YJ, Lai MZ. IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells. Nat Commun. 2018;9:463. 10.1038/s41467-018-02862-4.29386580 10.1038/s41467-018-02862-4
166. Seif F Torki Z Zalpoor H Habibi M Pornour M Breast cancer tumor microenvironment affects Treg/IL-17-producing Treg/Th17 cell axis: Molecular and therapeutic perspectives Mol Ther Oncolytics 2023 28 132 57 10.1016/j.omto.2023.01.001 36816749
Seif F, Torki Z, Zalpoor H, Habibi M, Pornour M. Breast cancer tumor microenvironment affects Treg/IL-17-producing Treg/Th17 cell axis: Molecular and therapeutic perspectives. Mol Ther Oncolytics. 2023;28:132–57. 10.1016/j.omto.2023.01.001.36816749 10.1016/j.omto.2023.01.001
167. Philippar U Lu T Vloemans N Bekkers M Van Nuffel L Gaudiano M Wnuk-Lipinska K Van Der Leede B-j Amssoms K Kimpe K Abstract 5690: Discovery of JNJ-67856633: a novel, first-in-class MALT1 protease inhibitor for the treatment of B cell lymphomas Cancer Res 2020 80 5690 5690 10.1158/1538-7445.Am2020-5690
Philippar U, Lu T, Vloemans N, Bekkers M, Van Nuffel L, Gaudiano M, Wnuk-Lipinska K, Van Der Leede B-j, Amssoms K, Kimpe K, et al. Abstract 5690: Discovery of JNJ-67856633: a novel, first-in-class MALT1 protease inhibitor for the treatment of B cell lymphomas. Cancer Res. 2020;80:5690–5690. 10.1158/1538-7445.Am2020-5690.10.1158/1538-7445.Am2020-5690
168. Keller P, Mazo IB, Gao Y, Reddy V, Caballero F, Stephens B, Marvin JE, Fu A, Sun Y, Jenkins RW et al. 1020P MPT-0118 a clinical drug candidate to assess Treg reprogramming via MALT1 blockade. Ann Oncol. 2021.
169. Bonazzi S d’Hennezel E Beckwith REJ Xu L Fazal A Magracheva A Ramesh R Cernijenko A Antonakos B Bhang HC Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy Cell Chem Biol 2023 30 235 e247212 10.1016/j.chembiol.2023.02.005 36863346
Bonazzi S, d’Hennezel E, Beckwith REJ, Xu L, Fazal A, Magracheva A, Ramesh R, Cernijenko A, Antonakos B, Bhang HC, et al. Discovery and characterization of a selective IKZF2 glue degrader for cancer immunotherapy. Cell Chem Biol. 2023;30:235–e247212. 10.1016/j.chembiol.2023.02.005.36863346 10.1016/j.chembiol.2023.02.005
170. Fujiwara Y Kato S Nesline MK Conroy JM DePietro P Pabla S Kurzrock R Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy Cancer Treat Rev 2022 110 102461 10.1016/j.ctrv.2022.102461 36058143
Fujiwara Y, Kato S, Nesline MK, Conroy JM, DePietro P, Pabla S, Kurzrock R. Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy. Cancer Treat Rev. 2022;110:102461. 10.1016/j.ctrv.2022.102461.36058143 10.1016/j.ctrv.2022.102461
171. Ladomersky E Zhai L Lenzen A Lauing KL Qian J Scholtens DM Gritsina G Sun X Liu Y Yu F IDO1 inhibition synergizes with Radiation and PD-1 blockade to Durably Increase Survival against Advanced Glioblastoma Clin Cancer Res 2018 24 2559 73 10.1158/1078-0432.Ccr-17-3573 29500275
Ladomersky E, Zhai L, Lenzen A, Lauing KL, Qian J, Scholtens DM, Gritsina G, Sun X, Liu Y, Yu F, et al. IDO1 inhibition synergizes with Radiation and PD-1 blockade to Durably Increase Survival against Advanced Glioblastoma. Clin Cancer Res. 2018;24:2559–73. 10.1158/1078-0432.Ccr-17-3573.29500275 10.1158/1078-0432.Ccr-17-3573
172. Wen L Lu H Li Q Li Q Wen S Wang D Wang X Fang J Cui J Cheng B Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis J Exp Clin Cancer Res 2019 38 299 10.1186/s13046-019-1185-0 31291983
Wen L, Lu H, Li Q, Li Q, Wen S, Wang D, Wang X, Fang J, Cui J, Cheng B, et al. Contributions of T cell dysfunction to the resistance against anti-PD-1 therapy in oral carcinogenesis. J Exp Clin Cancer Res. 2019;38:299. 10.1186/s13046-019-1185-0.31291983 10.1186/s13046-019-1185-0
173. Oweida A Hararah MK Phan A Binder D Bhatia S Lennon S Bukkapatnam S Van Court B Uyanga N Darragh L Resistance to Radiotherapy and PD-L1 Blockade is mediated by TIM-3 Upregulation and Regulatory T-Cell infiltration Clin Cancer Res 2018 24 5368 80 10.1158/1078-0432.Ccr-18-1038 30042205
Oweida A, Hararah MK, Phan A, Binder D, Bhatia S, Lennon S, Bukkapatnam S, Van Court B, Uyanga N, Darragh L, et al. Resistance to Radiotherapy and PD-L1 Blockade is mediated by TIM-3 Upregulation and Regulatory T-Cell infiltration. Clin Cancer Res. 2018;24:5368–80. 10.1158/1078-0432.Ccr-18-1038.30042205 10.1158/1078-0432.Ccr-18-1038
174. Champiat S Dercle L Ammari S Massard C Hollebecque A Postel-Vinay S Chaput N Eggermont A Marabelle A Soria JC Hyperprogressive Disease is a New Pattern of Progression in Cancer patients treated by Anti-PD-1/PD-L1 Clin Cancer Res 2017 23 1920 8 10.1158/1078-0432.Ccr-16-1741 27827313
Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, Chaput N, Eggermont A, Marabelle A, Soria JC, et al. Hyperprogressive Disease is a New Pattern of Progression in Cancer patients treated by Anti-PD-1/PD-L1. Clin Cancer Res. 2017;23:1920–8. 10.1158/1078-0432.Ccr-16-1741.27827313 10.1158/1078-0432.Ccr-16-1741
175. Champiat S Ferrara R Massard C Besse B Marabelle A Soria JC Ferté C Hyperprogressive disease: recognizing a novel pattern to improve patient management Nat Rev Clin Oncol 2018 15 748 62 10.1038/s41571-018-0111-2 30361681
Champiat S, Ferrara R, Massard C, Besse B, Marabelle A, Soria JC, Ferté C. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol. 2018;15:748–62. 10.1038/s41571-018-0111-2.30361681 10.1038/s41571-018-0111-2
176. Borcoman E Kanjanapan Y Champiat S Kato S Servois V Kurzrock R Goel S Bedard P Le Tourneau C Novel patterns of response under immunotherapy Ann Oncol 2019 30 385 96 10.1093/annonc/mdz003 30657859
Borcoman E, Kanjanapan Y, Champiat S, Kato S, Servois V, Kurzrock R, Goel S, Bedard P, Le Tourneau C. Novel patterns of response under immunotherapy. Ann Oncol. 2019;30:385–96. 10.1093/annonc/mdz003.30657859 10.1093/annonc/mdz003
177. Morad G Helmink BA Sharma P Wargo JA Hallmarks of response, resistance, and toxicity to immune checkpoint blockade Cell 2021 184 5309 37 10.1016/j.cell.2021.09.020 34624224
Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2021;184:5309–37. 10.1016/j.cell.2021.09.020.34624224 10.1016/j.cell.2021.09.020
178. Jacquelot N Yamazaki T Roberti MP Duong CPM Andrews MC Verlingue L Ferrere G Becharef S Vétizou M Daillère R Sustained type I interferon signaling as a mechanism of resistance to PD-1 blockade Cell Res 2019 29 846 61 10.1038/s41422-019-0224-x 31481761
Jacquelot N, Yamazaki T, Roberti MP, Duong CPM, Andrews MC, Verlingue L, Ferrere G, Becharef S, Vétizou M, Daillère R, et al. Sustained type I interferon signaling as a mechanism of resistance to PD-1 blockade. Cell Res. 2019;29:846–61. 10.1038/s41422-019-0224-x.31481761 10.1038/s41422-019-0224-x
179. Lee JC, Mehdizadeh S, Smith J, Young A, Mufazalov IA, Mowery CT, Daud A, Bluestone JA. Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis. Sci Immunol. 2020;5. 10.1126/sciimmunol.aba0759.
180. Haist M Mailänder V Bros M Nanodrugs Targeting T Cells in Tumor Therapy Front Immunol 2022 13 912594 10.3389/fimmu.2022.912594 35693776
Haist M, Mailänder V, Bros M. Nanodrugs Targeting T Cells in Tumor Therapy. Front Immunol. 2022;13:912594. 10.3389/fimmu.2022.912594.35693776 10.3389/fimmu.2022.912594
181. Ravi K Manoharan TJM Wang KC Pockaj B Nikkhah M Engineered 3D ex vivo models to recapitulate the complex stromal and immune interactions within the tumor microenvironment Biomaterials 2024 305 122428 10.1016/j.biomaterials.2023.122428 38147743
Ravi K, Manoharan TJM, Wang KC, Pockaj B, Nikkhah M. Engineered 3D ex vivo models to recapitulate the complex stromal and immune interactions within the tumor microenvironment. Biomaterials. 2024;305:122428. 10.1016/j.biomaterials.2023.122428.38147743 10.1016/j.biomaterials.2023.122428
182. Borna Š Lee E Nideffer J Ramachandran A Wang B Baker J Mavers M Lakshmanan U Narula M Garrett AK Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations Sci Transl Med 2023 15 eadg6822 10.1126/scitranslmed.adg6822 38117899
Borna Š, Lee E, Nideffer J, Ramachandran A, Wang B, Baker J, Mavers M, Lakshmanan U, Narula M, Garrett AK, et al. Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations. Sci Transl Med. 2023;15:eadg6822. 10.1126/scitranslmed.adg6822.38117899 10.1126/scitranslmed.adg6822
183. Golzari-Sorkheh M Zúñiga-Pflücker JC Development and function of FOXP3 + regulators of immune responses Clin Exp Immunol 2023 213 13 22 10.1093/cei/uxad048 37085947
Golzari-Sorkheh M, Zúñiga-Pflücker JC. Development and function of FOXP3 + regulators of immune responses. Clin Exp Immunol. 2023;213:13–22. 10.1093/cei/uxad048.37085947 10.1093/cei/uxad048
184. Arvey A van der Veeken J Samstein RM Feng Y Stamatoyannopoulos JA Rudensky AY Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells Nat Immunol 2014 15 580 7 10.1038/ni.2868 24728351
Arvey A, van der Veeken J, Samstein RM, Feng Y, Stamatoyannopoulos JA, Rudensky AY. Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat Immunol. 2014;15:580–7. 10.1038/ni.2868.24728351 10.1038/ni.2868
185. Nong L Zheng Y Li X Li D Liang L Wang W Li T The genetic deletion and protein expression of PRDM1 and its clinical implications in diffuse large B cell lymphoma: a retrospective cohort study in China Pathol Res Pract 2022 233 153860 10.1016/j.prp.2022.153860 35429891
Nong L, Zheng Y, Li X, Li D, Liang L, Wang W, Li T. The genetic deletion and protein expression of PRDM1 and its clinical implications in diffuse large B cell lymphoma: a retrospective cohort study in China. Pathol Res Pract. 2022;233:153860. 10.1016/j.prp.2022.153860.35429891 10.1016/j.prp.2022.153860
186. Ng MSF, Roth TL, Mendoza VF, Marson A, Burt TD. Helios enhances the preferential differentiation of human fetal CD4(+) naïve T cells into regulatory T cells. Sci Immunol. 2019;4. 10.1126/sciimmunol.aav5947.
187. Baine I Basu S Ames R Sellers RS Macian F Helios induces epigenetic silencing of IL2 gene expression in regulatory T cells J Immunol 2013 190 1008 16 10.4049/jimmunol.1200792 23275607
Baine I, Basu S, Ames R, Sellers RS, Macian F. Helios induces epigenetic silencing of IL2 gene expression in regulatory T cells. J Immunol. 2013;190:1008–16. 10.4049/jimmunol.1200792.23275607 10.4049/jimmunol.1200792
188. Sekiya T Hibino S Saeki K Kanamori M Takaki S Yoshimura A Nr4a receptors regulate Development and Death of Labile Treg precursors to prevent generation of pathogenic self-reactive cells Cell Rep 2018 24 1627 e16381626 10.1016/j.celrep.2018.07.008 30089271
Sekiya T, Hibino S, Saeki K, Kanamori M, Takaki S, Yoshimura A. Nr4a receptors regulate Development and Death of Labile Treg precursors to prevent generation of pathogenic self-reactive cells. Cell Rep. 2018;24:1627–e16381626. 10.1016/j.celrep.2018.07.008.30089271 10.1016/j.celrep.2018.07.008
189. Hiwa R, Nielsen HV, Mueller JL, Mandla R, Zikherman J. NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity. JCI Insight. 2021;6. 10.1172/jci.insight.151005.
190. Yang XP Jiang K Hirahara K Vahedi G Afzali B Sciume G Bonelli M Sun HW Jankovic D Kanno Y EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion Sci Rep 2015 5 10643 10.1038/srep10643 26090605
Yang XP, Jiang K, Hirahara K, Vahedi G, Afzali B, Sciume G, Bonelli M, Sun HW, Jankovic D, Kanno Y, et al. EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion. Sci Rep. 2015;5:10643. 10.1038/srep10643.26090605 10.1038/srep10643
191. Bamidele AO Svingen PA Sagstetter MR Sarmento OF Gonzalez M Braga Neto MB Kugathasan S Lomberk G Urrutia RA Faubion WA Jr. Disruption of FOXP3-EZH2 Interaction represents a Pathobiological mechanism in intestinal inflammation Cell Mol Gastroenterol Hepatol 2019 7 55 71 10.1016/j.jcmgh.2018.08.009 30510991
Bamidele AO, Svingen PA, Sagstetter MR, Sarmento OF, Gonzalez M, Braga Neto MB, Kugathasan S, Lomberk G, Urrutia RA, Faubion WA. Jr. Disruption of FOXP3-EZH2 Interaction represents a Pathobiological mechanism in intestinal inflammation. Cell Mol Gastroenterol Hepatol. 2019;7:55–71. 10.1016/j.jcmgh.2018.08.009.30510991 10.1016/j.jcmgh.2018.08.009
192. DuPage M Chopra G Quiros J Rosenthal WL Morar MM Holohan D Zhang R Turka L Marson A Bluestone JA The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation Immunity 2015 42 227 38 10.1016/j.immuni.2015.01.007 25680271
DuPage M, Chopra G, Quiros J, Rosenthal WL, Morar MM, Holohan D, Zhang R, Turka L, Marson A, Bluestone JA. The chromatin-modifying enzyme Ezh2 is critical for the maintenance of regulatory T cell identity after activation. Immunity. 2015;42:227–38. 10.1016/j.immuni.2015.01.007.25680271 10.1016/j.immuni.2015.01.007
193. Schoenhals JE Cushman TR Barsoumian HB Li A Cadena AP Niknam S Younes AI Caetano MDS Cortez MA Welsh JW Anti-glucocorticoid-induced tumor necrosis factor-related protein (GITR) therapy overcomes Radiation-Induced Treg Immunosuppression and drives Abscopal effects Front Immunol 2018 9 2170 10.3389/fimmu.2018.02170 30294332
Schoenhals JE, Cushman TR, Barsoumian HB, Li A, Cadena AP, Niknam S, Younes AI, Caetano MDS, Cortez MA, Welsh JW. Anti-glucocorticoid-induced tumor necrosis factor-related protein (GITR) therapy overcomes Radiation-Induced Treg Immunosuppression and drives Abscopal effects. Front Immunol. 2018;9:2170. 10.3389/fimmu.2018.02170.30294332 10.3389/fimmu.2018.02170
194. Gao Y You M Fu J Tian M Zhong X Du C Hong Z Zhu Z Liu J Markowitz GJ Intratumoral stem-like CCR4 + regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B J Hepatol 2022 76 148 59 10.1016/j.jhep.2021.08.029 34689996
Gao Y, You M, Fu J, Tian M, Zhong X, Du C, Hong Z, Zhu Z, Liu J, Markowitz GJ, et al. Intratumoral stem-like CCR4 + regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B. J Hepatol. 2022;76:148–59. 10.1016/j.jhep.2021.08.029.34689996 10.1016/j.jhep.2021.08.029
195. Yamagishi R Kamachi F Nakamura M Yamazaki S Kamiya T Takasugi M Cheng Y Nonaka Y Yukawa-Muto Y Thuy LTT Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma Sci Immunol 2022 7 eabl7209 10.1126/sciimmunol.abl7209 35749514
Yamagishi R, Kamachi F, Nakamura M, Yamazaki S, Kamiya T, Takasugi M, Cheng Y, Nonaka Y, Yukawa-Muto Y, Thuy LTT, et al. Gasdermin D-mediated release of IL-33 from senescent hepatic stellate cells promotes obesity-associated hepatocellular carcinoma. Sci Immunol. 2022;7:eabl7209. 10.1126/sciimmunol.abl7209.35749514 10.1126/sciimmunol.abl7209
196. Wu Y Mealer C Schutt S Wilson CL Bastian D Sofi MH Zhang M Luo Z Choi HJ Yang K MicroRNA-31 regulates T-cell metabolism via HIF1α and promotes chronic GVHD pathogenesis in mice Blood Adv 2022 6 3036 52 10.1182/bloodadvances.2021005103 35073581
Wu Y, Mealer C, Schutt S, Wilson CL, Bastian D, Sofi MH, Zhang M, Luo Z, Choi HJ, Yang K, et al. MicroRNA-31 regulates T-cell metabolism via HIF1α and promotes chronic GVHD pathogenesis in mice. Blood Adv. 2022;6:3036–52. 10.1182/bloodadvances.2021005103.35073581 10.1182/bloodadvances.2021005103
197. Zhang Y Feng ZP Naselli G Bell F Wettenhall J Auyeung P Ellis JA Ponsonby AL Speed TP Chong MM MicroRNAs in CD4(+) T cell subsets are markers of disease risk and T cell dysfunction in individuals at risk for type 1 diabetes J Autoimmun 2016 68 52 61 10.1016/j.jaut.2015.12.006 26786119
Zhang Y, Feng ZP, Naselli G, Bell F, Wettenhall J, Auyeung P, Ellis JA, Ponsonby AL, Speed TP, Chong MM, et al. MicroRNAs in CD4(+) T cell subsets are markers of disease risk and T cell dysfunction in individuals at risk for type 1 diabetes. J Autoimmun. 2016;68:52–61. 10.1016/j.jaut.2015.12.006.26786119 10.1016/j.jaut.2015.12.006
