==== Front Cell Biosci Cell Biosci Cell & Bioscience 2045-3701 BioMed Central London 37386520 1073 10.1186/s13578-023-01073-9 Review Overcoming acquired resistance to cancer immune checkpoint therapy: potential strategies based on molecular mechanisms Wang Bin wangbin_oncology@163.com 12 Han Yin hanyin_hy@126.com 3 Zhang Yuyu zhangyuyu@jlu.edu.cn 145 Zhao Qin jluzhaoqin09@jlu.edu.cn 123 Wang Huanhuan wanghh2714@mails.jlu.edu.cn 145 Wei Jinlong weijl17@mails.jlu.edu.cn 145 Meng Lingbin lingbin.meng@moffitt.org 6 Xin Ying xiny@jlu.edu.cn 7 http://orcid.org/0000-0002-4613-7438 Jiang Xin jiangx@jlu.edu.cn 145 1 grid.430605.4 0000 0004 1758 4110 Department of Radiation Oncology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021 China 2 grid.412901.f 0000 0004 1770 1022 Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041 China 3 grid.459428.6 Cancer Prevention and Treatment Institute of Chengdu, Department of Pathology, Chengdu Fifth People’s Hospital (The Second Clinical Medical College, Affiliated Fifth People’s Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu, 611137 China 4 grid.430605.4 0000 0004 1758 4110 Jilin Provincial Key Laboratory of Radiation Oncology & Therapy, The First Hospital of Jilin University, Changchun, 130021 China 5 grid.64924.3d 0000 0004 1760 5735 NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021 China 6 grid.468198.a 0000 0000 9891 5233 Department of Hematology and Medical Oncology, Moffitt Cancer Center, Tampa, FL 33612 USA 7 grid.64924.3d 0000 0004 1760 5735 Key Laboratory of Pathobiology, Ministry of Education, Jilin University, 126 Xinmin Street, Changchun, 130021 China 30 6 2023 30 6 2023 2023 13 12023 7 2022 15 6 2023 © The Author(s) 2023 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. Immune checkpoint inhibitors (ICIs) targeting CTLA-4 and PD-1/PD-L1 to boost tumor-specific T lymphocyte immunity have opened up new avenues for the treatment of various histological types of malignancies, with the possibility of durable responses and improved survival. However, the development of acquired resistance to ICI therapy over time after an initial response remains a major obstacle in cancer therapeutics. The potential mechanisms of acquired resistance to ICI therapy are still ambiguous. In this review, we focused on the current understanding of the mechanisms of acquired resistance to ICIs, including the lack of neoantigens and effective antigen presentation, mutations of IFN‐γ/JAK signaling, and activation of alternate inhibitory immune checkpoints, immunosuppressive tumor microenvironment, epigenetic modification, and dysbiosis of the gut microbiome. Further, based on these mechanisms, potential therapeutic strategies to reverse the resistance to ICIs, which could provide clinical benefits to cancer patients, are also briefly discussed. Keywords Immune checkpoint inhibitors Acquired resistance Mechanisms Tumor microenvironment Combination therapy the Education Department Foundation of Jilin Provincethe Jilin Provincial Science and Technology Foundations20210509003RQ 20210402002GH Jiang Xin the Health Talents Special Project of Jilin Provincial Finance DepartmentJLSWSRCZX2021-065 Jiang Xin the Program of Changchun Science and Technology Bureau development Plan Project21ZY29 Jiang Xin issue-copyright-statement© Society of Chinese Bioscientists in America (SCBA) 2023 ==== Body pmcIntroduction Over the last decade, the emergence of anticancer immunotherapies, especially immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), or PD-ligand 1(PD-L1) to boost tumor-specific T lymphocyte immunity, has opened a brand new chapter for treatment of multiple histological types of malignancies with durable responses and unsurpassed clinical efficacy [1]. Compared to chemotherapeutic agents or targeted therapies, ICIs are characterized by a persistent response that can be translated into long-term survival benefits. A pooled analysis from clinical trials revealed that advanced melanoma patients treated with ICIs, such as ipilimumab and pembrolizumab, exhibited durable clinical responses, as evidenced by a three-year survival rate of about 70% and an overall survival (OS) exceeding 10 years in over 21% patients [2, 3]. Despite the unprecedented durable responses and survival benefits that have been observed, the majority of patients are less sensitive to ICI monotherapy, demonstrating primary resistance. The objective response rates of ICI monotherapy seldom exceed 40% for most tumor types (and are generally much beneath this figure), with a large proportion of patients having a partial response [4–6]. And more worryingly, an encouraging initial decrease in overall tumor burden observed in a number of patients can be offset by the evolution of acquired resistance to ICI therapy, which eventually leads to radiological and/or clinical disease progression [7, 8]. A study showed that approximately 25% of melanoma patients developed acquired resistance following an initial response to pembrolizumab, with disease progression evident during the median follow-up of 21 months [9]. Another study also suggested that after a five-year follow-up, 39% of patients with melanoma who initially responded to nivolumab had disease progression [10]. Similarly, more than 30% non-small cell lung cancer (NSCLC) patients were found to have relapsed after an objective initial response to nivolumab at the 2-year follow-up [11]. Accordingly, the pooled analysis of four clinical trials of nivolumab in NSCLC patients revealed that up to 65% of responders had progressed at 4 years follow-up [12]. Several studies attempted to infer the incidence of acquired resistance by analyzing durable response data, ranging from 11 to 77% across different tumor types [13]. However, up to now, no uniform definition has been established for acquired resistance to ICI therapy. Although the immunotherapy resistance taskforce of the Society for Immunotherapy of Cancer (SITC) considered acquired resistance as the occurrence of disease progression in the setting of ongoing treatment in the patient who had previously achieved a documented, confirmed objective response or stable disease lasting for more than 6 months following antineoplastic therapy, the response evaluation criteria remain divided [8] As in contrast to primary resistance various mechanisms of which have been identified during the past decade, until recently, mechanisms of acquired resistance remain ambiguous, thereby few reliable predictive biomarkers and effective treatment options can be used in such patients [14]. In this review, we outlined the present understanding of mechanisms underlying acquired resistance to ICI therapy and briefly explored potential strategies to counter the resistance and improve overall outcomes from the perspective of resistant mechanisms. The cancer immunity cycle and acquired resistance to immune checkpoint inhibitors The process of anti-tumor immunity is a complex sequence of multiple steps, which can be defined as the “Cancer-Immunity Cycle” (Fig. 1). First, the released tumor-associated neoantigens are captured by the antigen-presenting cells (APCs), subsequently migrating to secondary lymphoid organs as well as to tumor-related tertiary lymphoid structures [15]. Second, the APCs process the captured neoantigens into immunogenic polypeptides and present them to CD8+ T cells via the binding of the antigen peptide-major histocompatibility complex class I (MHC-I) molecule complex on the APC surface and the T cell receptor (TCR) on the surface of native CD8+ T cells, which leads to the activation and proliferation of CD8+ T cells [16]. The engagement of costimulatory molecules, CD28 and B7, is a necessary condition for the complete activation of naive T cells, and is strictly regulated by inhibitory immune checkpoints like CTLA-4 or PD-1 and their ligands. Third, the activated CD8+ T‐cells home-in to the tumor by extravasating via the endothelium and infiltrating through the surrounding stromal tissue [17]. Lastly, the TCRs on the surface of infiltrating CD8+ T‐cells need to establish contact with the peptide MHC-I complexes on the surface of APCs to release perforin and lytic granules in the immune synapse, thereby mediating tumor destruction [18]. After tumor cells are eradicated, memory T cells are formed which keep quiescent until a re-exposure to the neoantigens [19]. Under natural conditions, immune checkpoints play a negative feedback role in regulating immune responses after T-cell activation. CTLA-4 on T cells binds to B7 ligands on APCs with much higher affinity and avidity than CD28, which competitively interferes with CD28-B7 interactions, thereby preventing costimulation at the T-cell-APC interface and inhibiting activation of T cell responses [20]. Interaction of PD-1 with its ligands (PD-L1/PD-L2) can inhibit the effector stage of T-cell activation, thus suppressing the immune response [6]. The continuous interaction between inhibitory and stimulatory signals promotes adaptive responses against tumor-associated neoantigens while avoiding autoimmunity [21]. It has been confirmed that various tumors escape T-cell killing by hijacking this mechanism, and antibodies directly targeting CTLA-4, PD-1, and PD-L1 have exhibited significant anti-tumor responses. Thus far, eight ICIs inhibitors for CTLA-4 (ipilimumab), PD-1 (nivolumab, pembrolizumab, cemiplimab, and dostarlimab), and PD-L1 (durvalumab, avelumab, and atezolizumab) have been approved by the U.S. Food and Drug Administration (FDA) for the management of over 20 cancer types, the clinical indications of which are given in Table 1 [22]. Relatlimab targeting the lymphocyte-activation gene 3 (LAG-3) received its first approval by the FDA for the treatment of metastatic or unresectable melanoma in March 2022 [23]. Agents inhibiting other immune checkpoints like are still in clinical testing [24]. Abnormalities in any step of the “Cancer-Immunity Cycle” during or after treatment can result in ICI acquired resistance.Fig. 1 Anti-tumor immune response and ICIs. The induction of the effective anti-tumor immune response requires multiple steps: (I) The tumor-associated neoantigens are released and subsequently captured by APCs; (II) APCs present the captured antigens on MHCI molecules to T-cells, resulting in the proliferation and activation of T-cells, (III) homing and infiltration of activated T-cells. (IV) recognition of peptide MHC-I complexes and release of perforin and lytic granules to mediate tumor cell killing. Abnormalities in each of these steps during or after treatment can develop acquired resistance to ICI therapy Table 1 Summary of FDA-approved immune checkpoint inhibitors Agent Manufacturer Target Molecular type FDA-Approved Application Trail(s) based Pembrolizumab (Keytruda) Merck & Co PD-1 An IgG4 kappa immunoglobulin Melanoma KEYNOTE-002 (NCT01704287) KEYNOTE-006 (NCT01866319) KEYNOTE‑054 (NCT02362594) NSCLC KEYNOTE‑042 (NCT02220894) KEYNOTE-189 (NCT02578680) KEYNOTE-407 (NCT03875092) KEYNOTE-021 (NCT02039674) KEYNOTE-010 (NCT01905657) HNSCC KEYNOTE-048 (NCT02358031) KEYNOTE-012 (NCT01848834) cHL KEYNOTE-204 (NCT02684292) KEYNOTE-087 (NCT02453594) PMBCL KEYNOTE-170 (NCT02576990) Urothelial carcinoma KEYNOTE-052 (NCT02335424) KEYNOTE-045 (NCT02256436) Colorectal cancer KEYNOTE-177 (NCT02563002) Gastric cancer KEYNOTE-811 (NCT03615326) Esophageal cancer KEYNOTE-590 (NCT03881111) KEYNOTE-181 (NCT03933449) Cervical cancer KEYNOTE-826 (NCT03635567) KEYNOTE 158 (NCT02628067) HCC KEYNOTE 224 (NCT02702414) MCC KEYNOTE-017 (NCT02267603) RCC KEYNOTE-426 (NCT02853331) KEYNOTE-581 (NCT02811861) KEYNOTE‑564 (NCT03142334) Endometrial carcinoma KEYNOTE 158 (NCT02628067) KEYNOTE-775 (NCT03517449) TMB-high cancer KEYNOTE 158 (NCT02628067) cSCC KEYNOTE-629 (NCT03284424) TNBC KEYNOTE-522 (NCT03036488) KEYNOTE-355 (NCT02819518) Nivolumab (Opdivo) Bristol-Myers Squibb PD-1 A human IgG4 monoclonal antibody Melanoma CHECKMATE-037 (NCT01721746) CHECKMATE-066 (NCT01721772) CHECKMATE-067 (NCT01844505) CHECKMATE-238 (NCT02388906) NSCLC CHECKMATE-227 (NCT02477826) CHECKMATE-816 (NCT02998528) CHECKMATE-9LA (NCT03215706) CHECKMATE-057 (NCT01673867) Malignant pleural mesotheliom CHECKMATE-743 (NCT02899299) RCC CHECKMATE-214 (NCT02231749) CHECKMATE-9ER (NCT03141177) CHECKMATE-025 (NCT01668784) cHL CHECKMATE-039(NCT01592370) SCCHN CHECKMATE-141(NCT02105636) Urothelial carcinoma CHECKMATE-274 (NCT02632409) CHECKMATE-275(NCT02387996) Colorectal cancer CHECKMATE-142 (NCT02060188) HCC CHECKMATE -040 (NCT01658878) Esophageal cancer CHECKMATE-577 (NCT02743494) CHECKMATE-648 (NCT03143153) CHECKMATE-649 (NCT02872116) ATTRACTION-3 (NCT02569242) Cemiplimab(Libtayo) Regeneron Pharmaceuticals PD-1 A recombinant human IgG4 monoclonal antibody CSCC Study 1423 (NCT02383212) Study 1540 (NCT02760498) Basal cell carcinoma Study 1620 (NCT03132636) NSCLC Study 1624 (NCT03088540) Dostarlimab (Jemperli) GlaxoSmithKline PD-1 An investigational humanized IgG4 monoclonal antibody Endometrial cancer GARNET (NCT02715284) solid tumors GARNET (NCT02715284), Atezolizumab (Tecentriq) Genentech PD-L1 An Fc-engineered, humanized, non-glycosylated IgG1 kappa immunoglobulin HCC IMbrave150(NCT03434379) Urothelial carcinoma IMvigor210 (NCT02108652) IMvigor130 (NCT02807636) NSCLC IMvigor010 (NCT02486718) IMpower110 (NCT02409342) IMpower150 (NCT02366143) IMpower130 (NCT02367781) OAK(NCT02008227) SCLC IMpower133(NCT02763579) Melanoma IMspire150 (NCT02908672) Durvalumab (Imfinzi) AstraZeneca PD-L1 A human IgG1 kappa monoclonal antibody SCLC CASPIAN(NCT03043872) NSCLC PACIFIC (NCT02125461) Urothelial carcinoma Study1108(NCT01693562) Avelumab(Bavencio) EMD Serono PD-L1 A human IgG1 lambda monoclonal antibody RCC JAVELIN Renal 101(NCT02684006) Urothelial carcinoma JAVELIN Solid Tumor (NCT01772004) MCC JAVELIN Merkel 200 (NCT02155647) Ipilimumab (Yervoy) Bristol-Myers Squibb CTL-4 An IgG1 kappa immunoglobulin HCC CHECKMATE-040 (NCT01658878) Colorectal cancer CHECKMATE-142 (NCT02060188) RCC CHECKMATE-214 (NCT02231749) Melanoma MDX010-20 (NCT00094653) Esophageal squamous cell carcinoma CHECKMATE-648 (NCT03143153) Malignant pleural mesothelioma CHECKMATE-743 (NCT02899299) NSCLC CHECKMATE-9LA (NCT03215706) CHECKMATE-227 (NCT02477826) Relatlimab-rmbw (Opdualag) Bristol-Myers Squibb LAG-3 A human IgG4 monoclonal antibody Melanoma RELATIVITY-047 (NCT03470922) Prepared using data from FDA.gov In contrast to primary resistance, acquired resistance is not clearly characterized across tumor types as its incidence has not been routinely reported [25]. Moreover, our understanding of acquired resistance is far from adequate and there is a desperate need to understand the mechanisms involving acquired resistance to determine the most optimal path forward for treating patients. Potential mechanisms underlying acquired resistance to immune checkpoint inhibitors The mechanisms of acquired resistance are indistinguishable and interdependent, and seem to overlap at least partially with the mechanisms of primary resistance. Pseudo-progression that occurs in the initial or late stage of treatment complicates the identification of resistance mechanisms. In light of Darwinian natural selection, the resistance to ICIs therapy may be pre-existing in the tumor cells before treatment, and is subsequently acquired as a result of the process of immune selection due to the genomic and epigenomic instability of tumor cells [7]. Acquired resistance may also occur at the individual tumor cell level because of the alternation in gene expression of tumor cells in response to interactions with immune cells or their products [7, 26]. Furthermore, the mechanisms leading to resistance might vary not only by tumor types but also by patient-specific factors due to the unique genetic and clinical backgrounds of each patient. Therefore, in this section, we have shed light on the current understanding of the mechanisms concerning acquired resistance in terms of tumor cell-intrinsic and cell-extrinsic factors, based on pre-clinical animal models and clinical trials (Fig. 2).Fig. 2 Graphical summary that explains underlying mechanism of acquired resistance to ICIs in terms of tumor cell-intrinsic and tumor cell-extrinsic factors. Tumor intrinsic mechanisms of acquired resistance involve loss of immunogenic antigens, defects in antigen processing and presentation, and mutations of IFN‐γ/JAK signaling pathway. Tumor extrinsic mechanisms of acquired resistance mainly include activation of alternate inhibitory immune checkpoints, immunosuppressive tumor microenvironment, epigenetic modification, and dysbiosis of the gut microbiome Tumor-intrinsic factors related to acquired resistance Loss of immunogenic neoantigens Neoantigens derived from somatic tumor non-synonymous mutations, which can be recognized by the immune system as “non-self”, are likely to be targets of tumor-specific T cells and elicit effective anti-tumor immune responses [21]. Tumor neoantigen burden is closely related to the immunogenicity and sensitivity to ICIs therapy [27]. Besides, tumors enriched with neoantigens have more abundant tumor-infiltrating cells (TILs) and higher levels of perforin mRNA and granzyme A, which is consistent with increased T-cell-mediated cytolytic activity [28]. Thus, mechanisms causing the loss of neoantigen expression during immunotherapy may lead to acquired resistance (Fig. 3). It has been proposed that cancer immunoediting comprises three sequential stages of elimination, equilibrium, and escape, which describe dynamic interactions between tumor cells and T cells [29]. Cancer immunoediting can lead to the partial or total elimination of neoantigens and the selection of subclones lacking neoantigen expression within the tumor, thereby conferring poor immunogenicity and acquired resistance to ICIs [29, 30]. A recent study by Anagnostou and colleagues was the first to demonstrate that acquired resistance to ICI therapy was related to the loss of mutations encoding putative mutation-associated neoantigens (MANAs) by eliminating tumor subclones or deleting chromosomal regions [31]. Specifically, whole-exome sequencing of matched resistant and pre-treatment tumors identified genomic alterations leading to the loss of 7 to 18 putative MANAs in resistant tumor clones from NSCLC patients who relapsed after an initial response to ICIs [31]. Acquired new mutations did not encode neoantigens, and the eliminated MANAs had higher predicted MHC binding affinity than either those that were gained or retained in the resistant tumors [31]. George et al. [32] identified the decreased expression of two neoantigens and loss of biallelic PTEN as the potential mechanisms of acquired resistance to ICI therapy by whole transcriptome analyses of pre-treatment and resistant tumor samples obtained from a uterine leiomyosarcoma patient. Moreover, it is arguable that the epitope of the CD19 protein sequence recognized by the chimeric antigen receptor may be selectively deleted at progression in some patients with acute lymphoblastic leukemia who demonstrated an initial response to CD19 adoptive T-cell therapy (ACT), and the pre-existing CD19 isoforms with alternative splicing may be prone to acquired resistance [33, 34].Fig. 3 Tumor cell-intrinsic factors contributing to acquired resistance to ICI therapy. A: Neoantigens are in partial or total eliminated conferring poor immunogenicity and acquired resistance to ICIs therapy. B: β2M mutations affect the presentation of peptide MHC-I complexes to T cells, thus leading to the tumor cells not being recognized by T cells. C: Mutations of JAK1 and JAK2 make the tumor cells insensitive to IFN-γ secreted by T-cells The pro-inflammatory cytokines produced by TILs may induce the loss of neoantigen expression contributing to acquired resistance [35]. An ACT-treated mouse model exhibited transient tumor response following the injection of T cells targeting the melanoma differentiation antigen gp100. Subsequently, inflammatory cytokine interferon-γ (IFN-γ) secreted by TILs triggered a process of melanoma cell de-differentiation akin to epithelial-to-mesenchymal transition (EMT), leading to adaptation of melanoma cells by reducing gp100 expression and switching to a less differentiated neural crest phenotype [36]. Other inflammatory cytokines like transforming growth factor-β (TGF-β) and interleukin-6 (IL-6) have been shown to mediate the neuroendocrine differentiation of numerous types of histological cancers like lung and prostate cancer by EMT, resulting in immune escape and acquired resistance [35, 37, 38]. Defects in antigen processing and presentation Neoantigens must be processed by APCs and presented to T cells in the form of peptide MHC-I complexes [39]. Thus, a decrease in mRNA transcription of MHC molecules, loss of genome, as well as mutations of the β-2-microglobulin (β2M) gene negatively affect antigen presentation and contribute to resistance to ICIs therapy [40] (Fig. 3). Paulson et al. [41] found a transcriptional loss of genes encoding MHC-I in two Merkel cell carcinoma patients whose tumors had relapsed after initial response to PD-1/PD-L1 inhibitors. Zaretsky and coworkers reported that acquired resistance to anti-PD-1/PD-L1 therapy was associated with a truncating mutation of the gene encoding β2M, which was related to MHC-I, and essential for its folding and transport to the surface of T cells [42, 43]. Immunohistochemical analysis of the MHC-I heavy chains in tumor samples obtained from the patient revealed that adventitial localization was lost when compared to pre-treatment tumor and adjacent stroma, despite continued production of MHC-I molecules in the recurrent tumor [43]. β2M aberrations including multiple early frameshift mutations, absence of tumor-specific β2M protein expression, and loss of heterozygosity overlapping β2M were reported to occur in about 30% of melanoma patients with progressive disease after anti-PD-1 therapy, leading to a total loss of MHC-I [44]. Knock-out of β2M in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in the resistance to ICIs [40]. Tran et al. [45] described the direct loss of the chromosome 6 haplotype encoding the HLA-C*08:02 in a patient with metastatic colorectal cancer that progressed after initial response to therapy consisting of HLA-C*08:02-restricted TILs targeting mutant KRAS G12D. Other mechanisms involved in the loss of MHC-I molecules have been reported, including downregulation of the transporter associated with antigen processing 2 and low‐molecular‐weight protein 7 in MSI‐negative colorectal tumors [46]. Furthermore, the increase in PD-1+ T cell infiltration is significantly related to the increase in β2M mutations, which indicates that the resistance induced by β2M mutations is associated with PD-1+ T cell infiltration. Mutations of IFN‐γ/JAK signaling pathway Mutations of the janus kinases 1 and 2 (JAK1/JAK2) in the downstream signaling pathway of IFN-γ are emerging as pivotal factors in acquired resistance to ICIs therapy (Fig. 3). IFN-γ secreted by tumor-specific T cells binds to the heterodimeric IFNGR1/IFNGR2 receptor complex on tumor cells and causes the activation of JAK1 and JAK2, which in turn phosphorylate a transcription factor known as signal transducer and activator of transcription (STAT) 1. Subsequently, the translocation of phosphorylated STAT1 homodimers to the nucleus modulates the transcription of IFN-γ stimulated genes, which increases the production of chemokines, thereby attracting immune cells and directly promoting tumor cell apoptosis [47, 48]. Additionally, IFN‐γ/JAK signaling can also induce proteasome subunits and transporters associated with MHC-I as well as upregulate expression of PD-L1, which enhances antigen presentation and response to PD-1 antibodies [49, 50]. Whole-exome sequencing of tumor tissues obtained at baseline (before therapy) and after disease progression from four melanoma patients who displayed disease progression after a median 1.8 years objective response to pembrolizumab, revealed that two of the patients exhibited over 90% truncating dysfunctional mutations in JAK1 (Q503* nonsense mutation) and JAK2 (F547 splice‐site mutation), concurrent with the deletion of the wild-type allele and duplication of the mutant allele [43]. The deactivation of JAK1 and JAK2 signaling led to acquired resistance to IFN‐γ, subsequently causing damage to immune surveillance and tumor cell proliferation [43]. Several studies have shown that the loss of JAK/STAT signaling leads to resistance to CTLA-4 and PD-1 inhibitors because of the inability to upregulate PD-L1 and MHC-I expression [48, 49, 51]. Of concern, loss-of-function mutations existing at high frequency in tumors may be associated with primary resistance to ICIs therapy, with pretreatment melanoma biopsies demonstrating IFN‐γ pathway mutations in as many as 19% of the samples [48, 52]. Mutations in this pathway could additionally lead to the loss of PD-L1 expression upon IFN-γ exposure, thereby causing resistance to inhibitors of PD-1/PD-L [48]. Mutations and deletions of IFN‐γ pathway-associated proteins, like IFNGR1 and IFNGR2, as well as STAT1, may also be a reason for resistance to ICIs and need to be further explored [52]. Tumor-extrinsic factors related to resistance Activation of alternate inhibitory immune checkpoints Overexpression of multiple alternate immune checkpoints contributing to a severely exhausted phenotype of T-cells can exert immunosuppressive effects and lead to the failure of ICI therapy. Acquired resistance to ICIs has been described secondary to compensatory upregulation of alternative immune checkpoints like T cell immunoglobulin and mucin domain 3 (TIM-3), LAG-3, B and T lymphocyte attenuator (BTLA), V-domain Ig suppressor of T cell activation (VISTA), T cell Ig and ITIM domain (TIGIT), and so on in multiple studies (Fig. 4). A study by Thommen et al. [53] revealed that increased coexpression of CTLA-4, PD-1, TIM-3, LAG-3 as well as BTLA, was positively related to progressive T-cell exhaustion and subsequent resistance to anti-PD1 therapy in NSCLC. Their research suggested that the surface of CD8+ T cells expressing the above five receptors had serious defects causing reduced proliferation, migration, and cytokine production. Koyama et al. [54] observed that TIM-3 up-regulation in TILs of lung adenocarcinoma patients was significantly correlated with acquired resistance to anti-PD-1 antibody. Moreover, the TIM-3 expression was related to the degree of anti-PD-1 antibody binding in T cells, the positive expression of which increased with the binding degree of T cells to anti-PD-1 blockade [54]. T-cells from resistant tumors also over-expressed LAG3 and CTLA4, however, BTLA expression appeared variable. Limagne et al. [55] demonstrated that the accumulation of monocytes, bone marrow-derived suppressor cells (MDSCs), and lymphocytes expressing TIM-3 and galectin-9 was related to primary or acquired resistance following nivolumab treatment in a cohort of NSCLC patients. Compared to matched pre-treatment tumors, the frequency of VISTA expression on T cells and CD68+ macrophages were found higher in treated prostate and melanoma tumors [56]. Kakavand et al. found that twelve melanoma patients with acquired resistance to ICIs were able to obtain matched samples before and after treatment, 8 of which patients were detected with VISTA upregulation [57]. Several studies suggested that the high expression of TIGIT regulatory T cells (Tregs) positively related to increased Treg frequencies in tumors and mediate tumor resistance to ICI therapy [58, 59]. The upregulation of other immune checkpoints also potentially results in acquired resistance that needs further research.Fig. 4 Immunosuppressive tumor microenvironment contributing to acquired resistance to ICI therapy. Immune cells infiltrate into the TME, interacting with each other and tumor cells, harbor an immunosuppressive phenotype responsible for immune escape of tumor cells and the following acquired resistance during or after ICI treatment. These immunosuppressive cells include Tregs, TAMs, MDSCs, which express the alternate inhibitory immune checkpoints like TIM-3, LAG-3, BTLA, VISTA, and TIGIT, secrete cytokines and growth factors like IL-35, IL-10, and TGF-β, VEGF, or product IDO and adenosine, which negatively regulate anti-tumor immune immunity, remodel the extracellular matrix, and promote angiogenesis. As a result, the immunosuppressive TME promotes the tumor cell resistance to ICI therapy Other suppressive factors in the tumor microenvironment (TME) It is now increasingly appreciated that immunosuppressive cells including Tregs, MDSCs, tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs), as well as some inhibitory cytokines, build a chronic inflammatory, pro-angiogenic, intratumoral, and immunosuppressive environment where tumor cells are liable to evade immune-mediated eradication and inhibit the therapeutic activity of ICIs [60–62] (Fig. 2). Tregs may be capable of suppressing the efficacy of effector T cells (TEFFs) by the secretion of some inhibitory cytokines like TGF-β, IL-10, and IL-35 [63, 64]. The response to PD-1/PD-L1 inhibitors has been shown to be correlated with an increased ratio of TEFFs to Tregs in murine models [65]. Simpson et al. [66] suggested that an increased Tregs infiltration resulted in acquired resistance to PD-1 inhibitors alone or in combination with radiotherapy. ICI treatment might cause the recruitment of Tregs to the TME and play a role in mediating resistance, as demonstrated in a murine model of claudin-low breast cancer generally known to be resistant to ICIs [67]. Timelines from clinical studies indicate that increased MDSCs in the TME promoting tumor invasion, angiogenesis, and metastasis correlate with the reduced efficacy of immunotherapies including ICIs [68, 69]. Previous clinical studies have revealed the relationship between increased infiltration of TAMs and ominous prognosis [31, 70]. TAMs can express co-inhibitory molecules, including PD-L1 and B7-H4, and release anti-inflammatory cytokines, such as IL-10 [71]. M2 macrophages were shown to directly remove anti-PD1 antibodies from the surface of PD-1+ T cells, thereby interfering with anti-PD1 therapy [70]. Thought to be one of the most abundant components in the mesenchyme of most tumors, CAFs contribute to T-cell dysfunction and immunosuppressive TME by producing several CAF-derived molecules and ligands, including IL-6, chemokine C-X-C motif ligand 12 (CXCL12), CXCL5, TGF-β, vascular endothelial growth factor (VEGF), fibronectin, and collagen, and the increased expression of immune checkpoint ligands including PD-L1, PD-L2, and FasL [72]. CAFs also promote a Dendritic cell (DC) phenotype that is unable to interact with and present antigens to CTLs [73]. Chakravarthy et al. identified a poor prognosis phenotype of CAFs driven mainly by the activation of TGF-β signaling, which was related to the PD-1 blockade resistance in bladder cancer and melanoma [74]. Increased infiltration of CAFs was related to resistance to PD-1 blockade, inhibition of which rescued the anti-tumor effects of anti-PD-1 treatment in mouse models of hepatocellular carcinoma [75]. Indole 2,3-dioxygenase (IDO), secreted by immune cells or tumor cells, can promote the secretion and activity of Tregs and MDSCs [76]. As a rate-limiting enzyme, IDO can promote the catabolism of tryptophan and generate immunosuppressive metabolites including kynurenine, thereby suppressing the function of T cells and inducing T cell apoptosis [77, 78]. Holmgaard et al. [79] reported that tumor growth was significantly delayed and OS markedly increased in IDO knockout melanoma mice treated with anti-PD1 therapy compared with that in wild-type mice. Also, the accumulation of extracellular adenosine though the HIF-1α-CD39/CD73-adenosine signaling pathway has been proven to drive an immunosuppressive TME, and promote tumor progression [80]. Influence of epigenetic modification Epigenetic modification of tumor cells has been shown to alter the expression of immune-associated genes, thus affecting the processing and presentation of antigens, proliferation, and differentiation of T cells, T-cell exhaustion, and acquisition of phenotype of memory T cells [81] (Fig. 5). Lower levels of IFN -γ and IFN-γ-induced genes like CXCL9 contribute to decreased infiltration of CD8+ T cells and are correlated with tumor progression following anti-PD-L1 therapy [82]. A study by Peng et al. [83] revealed that cancer epigenetic silencing consisting of enhancer of zeste homolog 2 (EZH2)-mediated histone modifications and DNA methyltransferase (DNMT) -mediated DNA methylation of the gene encoding the T helper 1-type chemokines, CXCL9 and CXCL10, decreased T cells homing and infiltration, thus potentially impairing the efficacy of immunotherapy. Recent studies have suggested that the exhaustion of T cells correlated with de novo DNA methylation and may persist and be passed on to successive T cell generations [84]. Epigenetic studies have suggested that although ICIs can reinvigorate exhausted CD8+ T cells (TEX) and enhance the control of chronic infections and tumors, they have little effect on genes related to the generation of memory T-cells [85]. They found that TEX metagenes treated with PD-L1 blockade partly overlapped with TEFF, but there was little overlap with memory T cells (TMEM), indicating that acquisition of memory potential was limited after TEX reinvigoration [85]. Reinvigorated TEX failed to become TMEM after antigen clearance and they became depleted again following anti-PD-L1 treatment, even if there was neoantigens re-exposure. Although the inhibition of the PD-1 pathway led to transcriptional re-wiring and re-engagement of effector circuitry in the TEX epigenetic landscape, TEX could never acquire the phenotype of memory T cells, and this epigenetic stability of TEX might result in acquired resistance to ICIs [85]. In addition, TEX showed extensive changes in the available chromatin, which were different from those in the TEFF counterparts. Exhaustion-specific enhancers in TEX displayed different motifs at T-bet, RAR, and Sox3 marker transcription factor binding sites. The crucial differences in the profile of regulatory regions between functional CD8+ T cells and TEX were greater than those observed in gene expression, which suggests that the accessible chromatin networks related to the exhaustion state required a large rewiring [86]. A combination of ICIs and epigenetic modifiers may help to improve the durability of the response to ICIs in the future.Fig. 5 Epigenetic modification and acquired resistance to ICI therapy. A: Epigenetic silencing of gene of T helper 1-type chemokines CXCL9 and CXCL10 results in CD8+ T cell homing and infiltration to the TME. B: Acquisition of memory potential was limited after reinvigoration of exhausted T cells with PD-L1 blockade. Reinvigorated exhausted T cells fail to become memory T cells after antigens clearance and they will become depleted again, even if neoantigens are exposed again Dysbiosis of gut microbiome It is emerging that the alteration of the human gut microbiome affects tumor progression and is connected with the response to ICIs therapy [87]. Significant differences in the structure of gut microbiome were observed between patients who responded well to ICIs and those who did not [88, 89]. A landmark study conducted by Gopalakrishnan et al. demonstrated that patients who have a high diversity and abundance of gut microbiota like Faecalibacterium and Ruminococcaceae have increased antigen presentation and improved TEFF function in the periphery and TME with enhanced anti-tumor immune response, whereas patients with low diversity and high relative abundance of gut microbiota like Bacteroidales have impaired anti-tumor immune responses mediated by a decreased capacity of antigen presentation and limited intratumoral lymphoid and myeloid infiltration [90]. G Analysis of the gut microbiome composition of patients with metastatic melanoma before anti-PD-1 treatment indicated that bacterial species including Ruminococcus obeum and Roseburia intestinalis were remarkably abundant in non-responders, while Enterococcus faecium, Collinsella aerofaciens, and Bifidobacterium longum were significantly enriched in responders [91]. A prospective study that enrolled 26 metastatic melanoma patients treated with ipilimumab found that antitumor response and immune-related colitis were related to colonization by Firmicutes including butyrate-producing bacterium L2–21, Faecalibacterium prausnitzii L2–6, and Gemmiger formicilis ATCC 27749. Compared to patients with initial microbiota enriched with Bacteroidetes, patients with microbiota rich in Faecalibacterium genus and other Firmicutes had a markedly higher progression-free survival (PFS) and OS [92]. Antibiotic use and gastrointestinal immune-related adverse events (irAEs), which are common complications of ICIs therapy, disrupt the intestinal microbiome and result in acquired resistance [93]. Pre-clinical mouse models have indicated that broad-spectrum antibiotics like imipenem and colistin eliminated gut microbiota and decreased the antitumor activity of CTLA-4 antibodies, with a significant reduction in the anti-CTLA-4-mediated sensitization of tumor-infiltrating and splenic lymphocytes. Bacteroides fragilis could recover the response to CTLA-4 antibodies, while tolerogenic Bacteroides species mediated complete resistance to CTLA-4 antibodies [94]. Also, clinical data from a large cohort of patients with non-small cell lung cancer, renal cell carcinoma, or urothelial cancer suggested that patients treated with antibiotics for routine indications shortly before, during, or shortly after treatment with anti-PD1/PD-L1 mAB had significantly lower PFS and OS rates compared to patients who had not received antibiotics, suggesting that disrupted the gut microbiota via antibiotic use could potentially impair anti-tumor immune responses and resulted in acquired resistance to ICIs [89]. The impact of gut microbiome alteration further increases the complexity of responsiveness and resistance to ICIs therapy. Large prospective trials are required to define the microbial components and mechanisms underlying this effect, and to provide a basis for introducing different kinds of gut bacteria to reverse immunotherapy resistance in cancer. Potential strategies to overcome resistance: combining immune checkpoint therapy with other therapies The above-mentioned mechanisms of acquired resistance to ICIs do not act in isolation, and the interactions between several immunosuppressive components and the overlap between various signaling pathways together resulted in resistance. Identifying the specific resistance mechanisms in these patients is a crucial step toward effective treatment and ultimately inducing durable responses for them. It is likely that combination therapies with multiple treatment modalities have potential synergistic effects and are likely to reverse resistance. It is worth noting that efforts should be guided by an understanding of the mechanisms underpinning resistance rather than the random combination with existing drugs and therapies. In this section, we discussed potential approaches to counter the resistance and improve the efficacy of ICIs from the perspective of the resistant mechanisms mentioned above (Table 2).Table 2 Summary of agents with potential to overcome acquired resistance to immune checkpoint inhibitors Category Agent Target combinational therapies Tumor type (s) Phase References Targeting neoantigen depletion Neo-PV-01 Personalized neoantigen-based vaccine Nivolumab Melanoma NSCLC Bladder Cancer Phase Ib (NCT02897765) [98] ISA 101 Synthetic long-peptide HPV-16 vaccine Nivolumab HPV-16-positive cancer Phase II (NCT02426892) [99] T-VEC Oncolytic virus Pembrolizumab Melanoma Phase Ib (NCT02263508) [102] T-VEC Oncolytic virus Ipilimumab Melanoma Phase II (NCT01740297) [103] T-VEC Oncolytic virus Ipilimumab; Nivolumab; Pembrolizumab Melanoma Retrospective [104] Targeting defects in antigen processing and presentation LCL161 The cIAP1/2 antagonist Anti-PD-L1 and/or anti-CTLA4 Pancreatic ductal adenocarcinoma Preclinical Trametinib The mall molecule MEK inhibitor Anti-PD-L1 HNSCC Preclinical [106] Chloroquine Inhibiting autophagy Anti-PD1 and anti-CTLA4 PDAC Preclinical [107] ASPIRE nanovaccine Specific pMHC-I, anti-PD1 antibody and B7 are simultaneously anchored by a programmed process NA Melanoma Colon carcinoma Lewis lung carcinoma Preclinical [108] Targeting IFN‐γ/JAK signaling pathway BO-112 A nanoplexed formulation of Poly I: C coupled to polyethylenimine Anti-PD-L1 Melanoma Preclinical [110] BO-112 A nanoplexed formulation of Poly I: C coupled to polyethylenimine Pembrolizumab; Nivolumab Solid tumor Phase I (NCT02828098) [111] Overexpression of NLRC5 Upexpressing NLRC5 ACT Melanoma Preclinical [112] Targeting alternate ICI activation F38-2E2 Anti-TIM-3 antibody Nivolumab Lung cancer Preclinical [55] Ieramilimab The LAG-3 inhibitor Spartalizumab Advanced malignancies Phase I/II (NCT02460224) [115] MIH63 Anti-VISTA antibody Anti-PD-1 and anti-CTLA-4 Squamous cell carcinoma Preclinical [116] Anti-murine BTLA antibody Anti-BTLA antibody Anti-PD-1 Glioblastoma Preclinical [117] Tiragolumab Anti-TIGIT antibody Atezolizumab NSCLC Phase II (NCT03563716) [118] Targeting suppressive tumor microenvironment anti-CD25 antibody Anti-CD25 antibody Anti-PD-1 Sarcoma, colon adenocarcinoma, melanoma, and colorectal carcinoma Preclinical [119] Mogamulizumab Anti-CCR4 antibody Nivolumab Solid tumors Phase I (NCT02476123) [121] PLX3397 CSF-1R kinase inhibitor Oncolytic viruses, and anti-PD-1 Colon cancer Preclinical [123] BLZ945 CSF-1R kinase inhibitor Anti-PD-1 and anti-PD-L1 Control spontaneous neuroblastoma Preclinical [124] ATRA Targeting MDSCs Anti-PD-1 NSCLC Preclinical [125] ATRA Targeting MDSCs Ipilimumab Melanoma Phase II (NCT02403778) [126] BMS-211 Targeting MDSCs anti-CTLA-4 Lung carcinoma, colon carcinoma, breast carcinoma and lymphoma Preclinical [127] Epacadostat The IDO1 enzyme inhibitor Pembrolizumab Solid tumors Phase I/II (NCT02178722) [128] Epacadostat The IDO1 enzyme inhibitor Pembrolizumab Melanoma Phase III (NCT02752074) [129] Linrodostat mesylate The IDO1 enzyme inhibitor Nivolumab Bladder cancer Phase I/II (NCT02658890) [130] CD39 knockout Blocking CD39 anti-PD1 HCC Preclinical [131] Oleclumab Anti-CD73 monoclonal antibody Durvalumab NSCLC Phase II (NCT05221840) [132] NIR178 The A2AR antagonist Immunotherapy NSCLC Phase II (NCT02403193) [133] TGFβ-blocking Inhibiting TGFβ Anti-PD-L1 Urothelial cancer Preclinical [134] Mithramycin Anti-PD-L1 Chronic lymphocytic leukemia Preclinical [135] Pegilodecakin The PEGylated form of IL10 Pembrolizumab or nivolumab Solid tumors Phase IB (NCT02009449) [136] Targeting epigenetic modification Decitabine The DNMT inhibitor anti-CTLA-4 Ovarian Cancer Preclinical [142] Azacitidine The DNMT inhibitor Nivolumab Acute Myeloid Leukemia Phase II (NCT02397720) [148] Panobinostat The HDAC inhibitor Anti-PD-L1 Melanoma Preclinical [143] Romidepsin The HDAC inhibitor Anti-PD-L1 Lung Adenocarcinoma Preclinical [144] HBI-8000 The HDAC inhibitor PD-1, PD-L1, or CTLA-4, Colon carcinoma and B-cell lymphoma Preclinical [145] Vorinostat The HDAC inhibitor Pembrolizumab NSCLC Phase I/Ib (NCT02638090) [149] Entinostat, The HDAC inhibitor Pembrolizumab Melanoma Phase Ib/II NCT02437136 [150] Entinostat The HDAC inhibitor Pembrolizumab NSCLC Phase Ib/II NCT02437136 [151] GSK503 The EZH2 inhibitor Anti-PD1, anti-CTLA-4 and IL-2 Melanoma Preclinical [146] Targeting gut microbiome Dysbiosis Bifidobacterium Regulating gut microbiota Anti-PD-L1 Melanoma Preclinical [153] Bacteroides fragilis Regulating gut microbiota Anti-CTLA-4 Melanoma Preclinical [94] Lactobacillus johnsonii, Bifidobacterium pseudolongum, and Olsenella Regulating gut microbiota Anti-CTLA-4 Colorectal cancer, bladder cancer, and melanoma Preclinical [154] EDP1503 Regulating gut microbiota Pembrolizumab Solid tumors Phase I/II (NCT03775850) [155] MRx0518 Regulating gut microbiota Pembrolizumab Bladder cancer, NSCLC, RCC, and Melanoma Phase I/II (NCT03637803) [156] FMT Regulating gut microbiota Anti-PD-1 Epithelial tumors Preclinical [89] FMT Regulating gut microbiota Nivolumab Melanoma Phase I NCT03353402 [157] FMT Regulating gut microbiota Pembrolizumab Melanoma Phase II NCT03341143 [158] Other emerging combination strategies STING-LNP Stimulating the STING pathway Anti-PD-1 Melanoma Preclinical [159] MUSIC platform Stimulating the STING pathway Anti-PD-1 Breast cancer Preclinical [160] iTPNCs Activating inflammatory signaling Anti-CTLA-4 Melanoma, colon cancer, and breast cancer Preclinical [161] 177Lu-PSMA-617 Delivering beta-particle radiation Pembrolizumab Prostate cancer Phase II NCT03805594 [162] BNT111 RNA vaccine Anti-PD-1 Melanoma Preclinical [163] 8FNs Nanovaccine Anti-PD-1 Melanoma Preclinical [164] Targeting neoantigen depletion It has been demonstrated that autologous tumor vaccinations enhancing immunogenicity and stimulating adaptive immune responses with tumor-specific antigens improved sensitivity to ICI therapy [95–97]. NEO-PV-01, a neoantigen-based vaccine, was tested combined with nivolumab in the phase Ib clinical trial (NCT02897765) in NSCLC, melanoma, and bladder cancer demonstrated that neoantigen-specific CD4+ and CD8+ T cell responses were detected in all vaccinated patients with no serious adverse events [98]. The combined therapy of the vaccine ISA 101 and nivolumab for patients with incurable HPV-16-positive tumors achieved an overall response rate of 33% and a median OS of 17.5 months, much higher than the results obtained with nivolumab monotherapy, rendering an overall response rate of 14.3% [99]. Guo et al. reported that neoantigen-loaded monocyte-derived dendritic cell vaccines in combination with nivolumab triggered neoantigen-specific CD4+ and CD8+ T cell activation and mediated complete regression of all tumors in advanced metastatic gastric cancer [100]. The combination of oncolytic virotherapy and ICI therapy is a promising approach. Similar to self vaccination, oncolytic virustherapy could also induce tumor antigen release and provide danger signals, which consequently led to enhanced T cell priming and ameliorated resistance to anti-PD1/PDL1 therapy [101]. Talimogene laherparepvec (T-VEC) has been proven to improve the efficacy of anti-PD-1 therapy in advanced melanoma patients, with an objective response rate of 62% and a complete response rate of 33% [102]. A phase II Study (NCT01740297) suggested that the combination of T-VEC and ipilimumab shows a higher objective response rate versus ipilimumab alone without additional safety concerns in patients with advanced unresectable melanoma [103]. Consistently, a retrospective study suggested that T-VEC treatment might overcome loco-regional ICI acquired resistance in patients with stage IIIB-IV M1c melanoma [104]. Targeting defects in antigen processing and presentation Growing evidence suggests that the correction of defects in antigen processing and presentation can greatly enhance the efficacy of ICI therapy. It was reported that the cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) antagonism controlled the growth of β2M deficient tumors, and was effective in models of either primary or acquired resistance to ICIs [105]. In a mouse model of MAPK-activated head and neck squamous cell carcinoma, trametinib, a small molecule MEK inhibitor, inhibited extracellular signal-regulated kinase phosphorylation, promoted MHC-I and PD-L1 expression, and in combination with PD-L1 blockade, overcame resistance to monotherapy, which significantly improved inhibition of tumor growth [106]. Results from a mouse model of pancreatic ductal adenocarcinoma showed that chloroquine enhanced MHC-I antigen expression, sensitizing tumors to dual immune checkpoint inhibition with anti-CTLA4 and anti-PD-1 antibodies [107]. The ASPIRE nanovaccine derived from recombinant adenovirus-infected dendritic cells, in which specific peptide-MHC-I, B7 co-stimulatory molecules, and anti-PD1 antibody were simultaneously anchored by a programmed process, could significantly enhance the delivery of antigen to lymphoid organs and induce broad-spectrum T-cell responses to eliminate established tumors [108]. Additionally, regimens targeting TLRs (e.g., TLR3, TLR9) have been shown to promote DC maturation and reasonably alleviate anti-PD1/PDL1 resistance [109]. Targeting the IFN‐γ/JAK signaling pathway In experiments in mice, intratumoral BO-112 (a nanoplexed formulation of Poly I: C coupled to polyethylenimine) exerted anti-tumor activities in an IFN-γ and IFN-α/β dependent manner, which was observed not only in locally injected tumors but also in distant tumors. And the systemic effect was augmented by the coadministration of anti–PD-L1 antibodies [110]. A multicenter phase I clinical trial (NCT02828098) incorporating 28 patients with tumors resistance to anti–PD-1 antibodies showed the combination of BO-112 administered intratumorally with pembrolizumab or nivolumab was also well-tolerated, with 3 patients achieved partial responses, with 10 more patients having stable disease, suggesting that local BO-112 might be a strategy to revert anti-PD-1 therapy [111]. ACT was effective against JAK2 loss tumors, but not JAK1 loss tumors in an IFN signaling-deficient model of B16 murine melanoma, and overexpression of NLRC5(nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) restored the efficacy of ACT against B16-JAK1 loss tumors [112]. Targeting activation of alternate inhibitory immune checkpoints The combination therapies of ICIs targeting different immune checkpoints indicate potential benefits in overcoming acquired resistance in pre-clinical studies and clinical trials. The combination of anti-CTLA-4 and anti-PD-1 treatment appears to target separate populations of T-cells and has already been approved in hepatocellular carcinoma, melanoma, renal cell carcinoma, and colorectal cancer, with a variety of trials ongoing [113, 114]. Limagne et.al suggested that TIM-3 blockade could restore in vitro the CD8 secreting property in PBMCs from lung cancer patients when used in combination with the anti-PD-1 antibody, suggesting that anti-TIM-3 reverses resistance to anti-PD-1 [55]. Phase I/II study (NCT02460224) suggested that the LAG-3 inhibitor ieramilimab plus anti-PD-1 spartalizumab were well tolerated and had anti-tumor activity, with elicited durable responses in 12 of 121 patients with solid malignancies [115]. Co-blockading PD-L1and VISTA in CT26 colon cancer and B16 melanoma mouse models showed better efficacy in inhibiting tumor growth and prolonging survival compared to targeting each molecule alone, suggesting a synergistic effect between anti-VISTA and anti-PD-L1 antibodies in inducing Teff activation [116]. Choi et al. showed that the combination of PD-1 blockade and BTLA inhibitier synergistically improved overall long-term survival compared to monotherapy, with decreased levels of Tregs and increased expression of CD4+ IFN-γ and CD8+ IFN-γ [117]. Interim data from a phase II trial (NCT03563716) demonstrated the improved efficacy of Dual inhibition of TIGIT and PD-L1 with tiragolumab and atezolizumab compared to atezolizumab alone in patients with PD-L1-positive metastatic NSCLC in terms of overall response and progression free survival without additional adverse events [118]. Targeting suppressive factors in the tumor microenvironment It seems that immunosuppress components within the TME represent promising targets for increasing the anti-tumor efficacy of immunotherapy. A pre-clinical study showed that anti-CD25 antibody could effectively deplete tumor-infiltrating Tregs and increase ratios of effector-to-Treg, and synergized with PD-1 blockade to promote complete tumor rejection [119]. It has been suggested that CC chemokine receptor 4 (CCR4) mediated Treg recruitment into the TME, antagonism of which could suppress the frequency of CCR4 reduced Tregs and potentiated anti-tumor efficacy of ICIs [120]. A phase I study (NCT02476123) showed that combining nivolumab, with mogamulizumab (a Treg-depleting anti-CCR4 antibody) provided an acceptable safety profile and anti-tumor activity, with populations of effector Tregs reduced and CD8+ T cells in TILs increased [121]. In the tumor TME, TAMs survival depends on the CSF1/CSF1R pathway, blocking CSF1/CSF1R has been proven to significantly reduce macrophage recruitment and M2 phenotype polarization and activates CD8+ T cells, thereby sensitizing tumor to ICI and prolonged survival in pancreatic ductal adenocarcinoma and hepatocellular carcinoma [122]. Results according to mouse models of colon cancer revealed that CSF-1R kinase inhibitor PLX3397 combined with anti-PD-1 antibody and oncolytic viruses synergistically conferred significant tumor control and prolonged the survival [123]. Antagonizing CSF-1R with BLZ945 could reduce the induction of human and murine suppressive myeloid cells, when combined with PD-(L)1 blockades superiorly limited tumor progression [124]. Due to the function of modulating the differentiation of MDSCs, the combinational therapies of ATRA and immunotherapies have synergistic anti-tumor efficacy. Depleting MDSCs by all-trans-retinoic acid (ATRA) in the model of LKB1-deficient murine tumors resulted in improved anti-tumor T cell responses and increased sensitivity to PD-1 blockade [125]. Randomized phase II clinical trial (NCT02403778) reported that ATRA plus ipilimumab significantly decreased the number of MDSCs in the peripheral circulation of patients with metastatic melanoma without increased incidence of grade 3 or 4 adverse events, compared with ipilimumab monotherapy [126]. Besides, inhibition of casein kinase 2 (CK2) with BMS-211 substantially reduced the amount of polymorphonuclear MDSCs and macrophage differentiation, which was dramatically synergized with the anti-tumor efficacy of CTLA-4 blockades [127]. The phase I/II ECHO-202/KEYNOTE-037 trial (NCT02178722) revealed that epacadostat (a selective IDO1 enzyme inhibitor) plus pembrolizumab generally had a manageable safety profile and encouraging anti-tumor activity in several advanced solid tumors like melanoma, NSCLC, squamous cell carcinoma of the head and neck, renal cell carcinoma, urothelial carcinoma, and endometrial adenocarcinoma [128]. Nevertheless, epacadostat had no additional clinical benefit to pembrolizumab in the pivotal phase III study [129]. A Phase I/II trial (NCT02658890) suggested that linrodostat mesylate (an oral IDO1 inhibitor) in combination with nivolumab has demonstrated safety and preliminary evidence of clinical activity, with an ORR of 34% in the advanced bladder cancer [130]. Several preclinical studies have implicated that unleashing the immunosuppressive TME by targeting CD39/CD73 (that generate adenosine) and anti- adenosine agents (that consume adenosine) could suppress acquired resistance thus synergy ICIs efficacy [121]. Lu et.al has demonstrated that targeting CD39 on macrophages could efficiently rescue anti-PD1 resistance in hepatocellular carcinoma (HCC) [131]. The phase II trial of Oleclumab targeting CD73 in combination with Durvalumab showed prolonged PFS and increased ORR versus durvalumab alone, with manageable safety profiles [132]. Results from the phase I/II study of the A2AR antagonist NIR178 in advanced NSCLC suggested that clinical benefit was observed in immunotherapy-exposed and -naïve patients regardless of PD-L1 status, and was well tolerated [133]. A number of such combination therapies are currently ongoing in clinical trials. Moreover, vascular normalization with VEGF/VEGFR inhibitors combined with PD-(L)1 blockade has demonstrated clinical efficacy across a variety of tumor types in phase III trials and is already FDA-approved in NSCLC, renal cell carcinoma (RCC), endometrial carcinoma, and hepatocellular carcinoma. Furthermore, co-blockade of TGF-β and PD-L1 was shown to reduce TGF-β signaling in stromal cells, facilitate T-cell infiltration into the tumor centers, provoking vigorous anti-tumor immunity and tumor regression [134]. Trials evaluating the combined inhibition of TGF-β and PD-(L)1 in a variety of solid tumors are underway (NCT04390763, NCT02423343). Compared to anti-PD-L1 alone, IL-10 inhibition improved responses to anti-PD-L1 and produced more cytotoxic effector KLRG1+, IFN-γ+, and memory CD8+ T-cells, and fewer exhausted T-cells in chronic lymphocytic leukemia [135]. In contrast, pegilodecakin (pegylated IL-10) has been tested in a clinical trial (NCT02009449) and demonstrated to have a manageable toxicity profile and preliminary anti-tumor activity when in combination with pembrolizumab or nivolumab in previously treated advanced RCC [136]. Hypoxia within the TME is an intrinsic property of all solid malignant tumors, and we have detailed how to target hypoxic TME synergistically with immunotherapy in another review [80]. The induction of tertiary lymphoid structures (TLSs) that represent local and favorable sites for generating antitumor humoral and cellular immune responses has been shown to be capable of overcoming resistance to ICIs [137, 138]. A number of such combination therapies are currently ongoing in clinical trials. Targeting epigenetic modification Epi-drugs, defined as small-molecule inhibitors that target epigenetic regulators like DNMT, HDAC, and EZH2, have been shown to augment anti-tumor immune responses through multiple immunomodulatory activities [139, 140]. In animal models of breast, colon, and prostate cancers, inhibition of DNMT led to MHC-I upregulation, T-cell chemotaxis, and tumor infiltration of CD8+ T cells, thus enhancing the anti-tumor effects of anti-PD-1 antibodies [141]. Decitabine (a related DNMT inhibitor) stimulated the cytotoxic and infiltration responses of CD8+ T cells, which combined with anti-CTLA-4 antibody exhibited synergistic anti-tumor effects and extended survival in a syngeneic murine ovarian cancer model [142]. Panobinostat, an HDAC inhibitor, could upregulate the expression of PD-L1 and PD-L2 and improve anti-PD-1 immunotherapy in melanoma, resulting in improved inhibition of tumor growth and increased survival compared to anti-PD1 monotherapy [143]. Romidepsin was demonstrated to induce strong anti-tumor responses in a T cell-dependent manner and combinatory therapy with anti-PD-1 and induce tumor rejection in multiple lung tumor models [144]. Several preclinical models suggested that a novel orally bioavailable HDAC inhibitor HBI-8000 could augment the activity of ICIs targeting either PD-1, PD-L1, or CTLA-4, and significantly reduce tumor progression [145]. It has been shown that inhibiting EZH2 reversed acquired resistance and enhanced anti-tumor effects when in combination with anti-PD1, anti-CTLA-4, and IL-2 immunotherapy in prostate cancer and melanoma [146, 147]. Inspired by the encouraging results of preclinical studies, the combination therapy of ICIs with epigenetic drugs is being translated into clinical trials. A phase II trial (NCT02397720) revealed that the combination of azacitidine and nivolumab was safe and produced encouraging objective response rate and OS outcomes in patients with acute myeloid leukemia [148]. In phase I/Ib trial (NCT02638090), HDAC inhibitor vorinostat plus pembrolizumab was well tolerated and demonstrated preliminary anti-tumor activity, with three confirmed partial response (PR) and eleven stable disease responses among ICI-resistant metastatic NSCLC 24 patients [149]. Furthermore, preliminary results from the ENCORE-601 phase Ib/II trial revealed that entinostat, an experimental HDAC inhibitor, was well tolerated and, together with pembrolizumab, induced durable responses in melanoma patients whose disease progressed after PD-1 blockade monotherapy [150]. However, entinostat plus pembrolizumab provided a clinically meaningful benefit despite not achieving the primary response rate endpoint in the expansion cohort of ENCORE 601 that included anti-PD-(L)1-experienced patients with NSCLC [151]. Additionally, trials of EZH2 inhibitors plus pembrolizumab or ipilimumab are recruiting the patients with advanced solid tumors (NCT03854474 and NCT03525795). Together, these results provided a solid rationale for combining epigenetic agents with ICI immunotherapy. Targeting gut microbiome dysbiosis Manipulating the gut microbiota has been shown to enhance anti-tumor immunity and alleviate the development of acquired resistance to ICIs [94, 152]. Sivan et.al first revealed that commensal Bifidobacterium can enhance anti-tumor immunity in vivo in a non-antigen-dependent manner, which exhibited synergistic anti-tumor effectiveness with PD-L1 inhibitor [153]. It was reported that oral feeding of Bacteroides fragilis with Burkholderia cepacian or Bacteroides thetaiotaomicron enhanced the efficacy of CTLA-4 blockade via promoting DC maturation and triggering Th1 immune responses [94]. Three bacterial species (Lactobacillus johnsonii, Bifidobacterium pseudolongum, and Olsenella) were found to significantly enhanced efficacy and promote ICI therapies by raising the activation of CD4+ and CD8+ T cells [154]. A study conducted in a mouse model suggested that the presence of A. muciniphila and Akkermansia muciniphila contributed to the immunogenicity of the PD-1 blockade, and its abundance was related to clinical responses. Fecal microbiota transplantations (FMT) restored the efficacy of anti-PD-1 blockade in an IL-12-dependent manner [89]. Motivated by the encouraging results of preclinical studies, numerous clinical trials focusing on how to modulate gut microbiota composition to overcome ICI resistance are ongoing. A phase I/II clinical trial (NCT03775850) revealed that EDP1503 (an oral microbiota product) combined with pembrolizumab was well-tolerated and safe, and biomarker analysis found that EDP1503 works though upregulating the CD8+ T cells/Treg cell ratio [155]. Results of the phase I/II trial (NCT03637803) investigating the synergistic efficacy of the oral probiotic MRx0518 combined with pembrolizumab in bladder cancer, NSCLC, RCC, or melanoma have not yet been published [156]. Results from two recent clinical trials (NCT03353402 and NCT03341143) have suggested that patients with metastatic melanoma-resistant to PD-1 inhibitor after the intervention of FMT from responders had improved clinical benefits [157, 158]. Other emerging combination strategies Besides discussed above, multiple emerging strategies combined with ICIs are underway, some of which reported early encouraging results. The stimulator of an interferon gene agonist-loaded lipid nanoparticles (STING-LNP) might represent a promising candidate for anti-PD-1-resistant tumors, which in combination with PD-1 blockade synergistically promoted anti-tumor response via the activation of NK cells to overcome anti-PD-1 resistance in a B16-F10 lung metastasis model [159]. Similarly, Li et al. reported that novel Microbubble-assisted UltraSound-guided Immunotherapy of Cancer (MUSIC) platform utilized antibody guided targeting to stimulating STING pathway in APCs, further sensitizing poorly immunogenic tumors to anti-PD-1 therapy [160]. Engineered nanoparticles carrying immunostimulatory oligonucleotides has been confirmed to synergize with anti-CTLA-4 therapy to achieve tumor suppression in animal models of melanoma, colon cancer, and breast cancer [161]. The tumor-targeted radioligand 177Lu-PSMA-617 has recently demonstrated anti-tumor activity in prostate cancer [162], and its synergy with anti–PD-1 is currently being investigated in a phase II trial (NCT03805594). In addition, the SARS-CoV-2 pandemic has enormously unlocked the potential of vaccine technology as a powerful therapeutic platform. Phase I trail (NCT02410733) suggested that BNT111 (an intravenously administered liposomal RNA vaccine), alone or in combination with PD1 blockade, mediated durable objective responses in ICI-experienced patients with unresectable melanoma [163]. Moreover, an exciting preclinical study demonstrated the vaccination of 8p4 + FK-33 nanoparticles (8FNs) incorporating different tumor antigens could inhibit tumor growth by reversing the immunosuppressive TME and potentiating anti-tumor immunity, exerting synergistic therapeutic effects with PD-1 inhibitor [164]. We hoped that the development of more emerging strategies could pave the way for overcoming resistance to ICI therapy. Future perspectives and conclusions Although ICI therapy has revolutionized medical oncology, the emergence of acquired resistance in a considerable proportion of patients poses a significant challenge. Currently, the true landscape of acquired resistance to ICIs remains largely uncertain, thus the uniform definition and evaluation criteria are required to be established for acquired resistance. Moreover, emerging multifaceted approaches and higher resolution investigations of interactions involving host, tumor, and/or the TME may aid in the discovery new resistant mechanisms and predict new synergistic combinations. As ongoing research into underlying biology of acquired resistance to ICI therapy, the near future will witness more and more therapeutic combinations to overcome acquired resistance, resulting in clinical benefits for more patients. However, given the heterogeneity of tumor types and the complexity of anti-tumor immune responses, a wide set of biomarkers, such as TILs status, TMB, TLS, and PD-L1 expression, is required to predict the treatment efficacy or resistance to ICIs. With the development of human bioinformatic analysis and genome sequencing, more and more patients will definitely benefit from both integrated and individualized immunotherapies. Abbreviations ICIs Immune checkpoint inhibitors CTLA-4 Cytotoxic T lymphocyte antigen 4 PD-1 Programmed death 1 PD-L1 PD-ligand 1 OS Overall survival NSCLC Non-small cell lung cancer SITC The Society for Immunotherapy of Cancer APCs Antigen-presenting cells MHC-I Major histocompatibility complex class I TCR T cell receptor FDA Food and Drug Administration LAG3 Lymphocyte-activation gene 3 TILs Tumor-infiltrating cells ACT Adoptive T-cell therapy MANAs Mutation-associated neoantigens IFN-γ Interferon-γ EMT Epithelial-to-mesenchymal transition TGF-β Transforming growth factor-β IL-6 Interleukin-6 β2M β-2-Microglobulin JAK1/JAK2 Janus kinases 1 and 2 STAT Signal transducer and activator of transcription TIM3 T-cell immunoglobulin and mucin domain 3 BTLA B and T lymphocyte attenuator VISTA V-domain Ig suppressor of T cell activation TIGIT T cell Ig and ITIM domain MDSCs Marrow-derived suppressor cells Tregs Regulatory T cells TAMs Tumor-associated macrophages; CAFs Cancer-associated fibroblasts BTLA B and T lymphocyte attenuator TEFF Effector T cells CXCL12 Chemokine C-X-C motif ligand 12 VEGF Vascular endothelial growth factor DC Dendritic cell IDO Indole 2,3-dioxygenase PFS Progression-free survival EZH2 Zeste homolog 2 DNMT DNA methyltransferase TEX Exhausted CD8+ T cells TMEM Memory T cells irAEs Immune-related adverse events RCC Renal cell carcinoma; T-VEC Talimogene laherparepvec cIAP1/2 Cellular inhibitor of apoptosis proteins 1 and 2 NLRC5 Nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5 CCR4 CC chemokine receptor 4 ATRA All-trans-retinoic acid CK2 Casein kinase 2 HCC Hepatocellular carcinoma TLSs Tertiary lymphoid structures SCL Small cell lung cancer HNSCC Head and neck squamous cell carcinoma cHL Classical hodgkin lymphoma PMBCL Primary mediastinal large B cell lymphoma MCC Merkel cell carcinoma TMB Tumor mutational burden CSCC Cutaneous squamous cell carcinoma TNBC Triple-negative breast cancer PDAC Pancreatic ductal adenocarcinoma STING-LNP The stimulator of an interferon gene agonist-loaded lipid nanoparticles MUSIC Microbubble-assisted UltraSound-guided Immunotherapy of Cancer iTPNCs Immunostimulatory tandem peptide nanocomplexes 8FNs 8P4 + FK-33 nanoparticles Acknowledgements We would like to thank Editage (www.editage.cn) for English language editing. Author contributions Conceptualization, BW and XJ; software, investigation, BW, QZ, and HHW; resources, YYZ and JLW; writing-original draft preparation, BW, and YH; writing—review and editing, BW, RJ, YX, and XJ; funding acquisition, XJ. All authors read and approved the manuscript. Funding This research was funded in part by grants from the Health Talents Special Project of Jilin Provincial Finance Department (JLSWSRCZX2021-065), the Program of Changchun Science and Technology Bureau development Plan Project (21ZY29), the Education Department Foundation of Jilin Province (JJKH20211195KJ) and the Jilin Provincial Science and Technology Foundations (20210509003RQ and 20210402002GH). Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Competing interests The authors declare no conflict of interest. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Bin Wang and Yin Han contributed equally to this work. ==== Refs References 1. Bagchi S Yuan R Engleman EG Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance Annu Rev Pathol 2021 16 223 249 10.1146/annurev-pathol-042020-042741 33197221 2. Schadendorf D Hodi FS Robert C Pooled analysis of long-term survival data from phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma J Clin Oncol 2015 33 17 1889 1894 10.1200/JCO.2014.56.2736 25667295 3. Robert C Long GV Brady B Nivolumab in previously untreated melanoma without BRAF mutation N Engl J Med 2014 372 4 320 330 10.1056/NEJMoa1412082 25399552 4. Topalian SL Hodi FS Brahmer JR Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N Engl J Med 2012 366 26 2443 2454 10.1056/NEJMoa1200690 22658127 5. Hamid O Robert C Daud A Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma N Engl J Med 2013 369 2 134 144 10.1056/NEJMoa1305133 23724846 6. Zou W Wolchok JD Chen L PD-L1 (B7–H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations Sci Transl Med. 2016 8 328 328rv4 10.1126/scitranslmed.aad7118 26936508 7. Restifo NP Smyth MJ Snyder A Acquired resistance to immunotherapy and future challenges Nat Rev Cancer 2016 16 2 121 126 10.1038/nrc.2016.2 26822578 8. Kluger HM Tawbi HA Ascierto ML Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce J Immunother Cancer 2020 8 1 e000398 10.1136/jitc-2019-000398 32238470 9. Ribas A Hamid O Daud A Association of pembrolizumab with tumor response and survival among patients with advanced melanoma JAMA 2016 315 15 1600 1609 10.1001/jama.2016.4059 27092830 10. Larkin J Chiarion-Sileni V Gonzalez R Five-year survival with combined nivolumab and ipilimumab in advanced melanoma N Engl J Med 2019 381 16 1535 1546 10.1056/NEJMoa1910836 31562797 11. Horn L Spigel DR Vokes EE Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III Trials (CheckMate 017 and CheckMate 057) J Clin Oncol 2017 35 35 3924 3933 10.1200/JCO.2017.74.3062 29023213 12. Antonia SJ Borghaei H Ramalingam SS Four-year survival with nivolumab in patients with previously treated advanced non-small-cell lung cancer: a pooled analysis Lancet Oncol 2019 20 10 1395 1408 10.1016/S1470-2045(19)30407-3 31422028 13. Schoenfeld AJ Hellmann MD Acquired resistance to immune checkpoint inhibitors Cancer Cell 2020 37 4 443 455 10.1016/j.ccell.2020.03.017 32289269 14. Morad G Helmink BA Sharma P Hallmarks of response, resistance, and toxicity to immune checkpoint blockade Cell 2021 184 21 5309 5337 10.1016/j.cell.2021.09.020 34624224 15. Chen DS Mellman I Oncology meets immunology: the cancer-immunity cycle Immunity 2013 39 1 1 10 10.1016/j.immuni.2013.07.012 23890059 16. Becht E Giraldo NA Dieu-Nosjean MC Cancer immune contexture and immunotherapy Curr Opin Immunol 2016 39 7 13 10.1016/j.coi.2015.11.009 26708937 17. Sharma P Allison JP The future of immune checkpoint therapy Science 2015 348 6230 56 61 10.1126/science.aaa8172 25838373 18. O'Donnell JS Long GV Scolyer RA Resistance to PD1/PDL1 checkpoint inhibition Cancer Treat Rev 2017 52 71 81 10.1016/j.ctrv.2016.11.007 27951441 19. Ribas A Shin DS Zaretsky J PD-1 blockade expands intratumoral memory T cells Cancer Immunol Res 2016 4 3 194 203 10.1158/2326-6066.CIR-15-0210 26787823 20. Schildberg FA Klein SR Freeman GJ Coinhibitory pathways in the B7-CD28 ligand-receptor family Immunity 2016 44 5 955 972 10.1016/j.immuni.2016.05.002 27192563 21. Schumacher TN Schreiber RD Neoantigens in cancer immunotherapy Science 2015 348 6230 69 74 10.1126/science.aaa4971 25838375 22. Vesely MD Zhang T Chen L Resistance Mechanisms to Anti-PD Cancer Immunotherapy Annu Rev Immunol 2022 40 45 74 10.1146/annurev-immunol-070621-030155 35471840 23. Paik J Nivolumab plus relatlimab: first approval Drugs 2022 82 8 925 931 10.1007/s40265-022-01723-1 35543970 24. Mahoney KM Rennert PD Freeman GJ Combination cancer immunotherapy and new immunomodulatory targets Nat Rev Drug Discovery 2015 14 8 561 584 10.1038/nrd4591 26228759 25. Zhou B Gao Y Zhang P Acquired Resistance to Immune Checkpoint Blockades: The Underlying Mechanisms and Potential Strategies Front Immunol 2021 12 693609 10.3389/fimmu.2021.693609 34194441 26. Pardoll D Cancer and the immune system: basic concepts and targets for intervention Semin Oncol 2015 42 4 523 538 10.1053/j.seminoncol.2015.05.003 26320058 27. Kvistborg P van Buuren MM Schumacher TN Human cancer regression antigens Curr Opin Immunol 2013 25 2 284 290 10.1016/j.coi.2013.03.005 23566921 28. Van Allen EM Miao D Schilling B Genomic correlates of response to CTLA-4 blockade in metastatic melanoma Science 2015 350 6257 207 211 10.1126/science.aad0095 26359337 29. O'Donnell JS Teng MWL Smyth MJ Cancer immunoediting and resistance to T cell-based immunotherapy Nat Rev Clin Oncol 2019 16 3 151 167 10.1038/s41571-018-0142-8 30523282 30. Matsushita H Vesely MD Koboldt DC Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting Nature 2012 482 7385 400 404 10.1038/nature10755 22318521 31. Anagnostou V Smith KN Forde PM Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer Cancer Discov 2017 7 3 264 276 10.1158/2159-8290.CD-16-0828 28031159 32. George S Miao D Demetri GD Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma Immunity 2017 46 2 197 204 10.1016/j.immuni.2017.02.001 28228279 33. Ruella M Barrett DM Kenderian SS Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies J Clin Investig 2016 126 10 3814 3826 10.1172/JCI87366 27571406 34. Larkin J Chiarion-Sileni V Gonzalez R Combined nivolumab and ipilimumab or monotherapy in untreated melanoma N Engl J Med 2015 373 1 23 34 10.1056/NEJMoa1504030 26027431 35. Ribas A Adaptive immune resistance: how cancer protects from immune attack Cancer Discov 2015 5 9 915 919 10.1158/2159-8290.CD-15-0563 26272491 36. Landsberg J Kohlmeyer J Renn M Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation Nature 2012 490 7420 412 416 10.1038/nature11538 23051752 37. Knutson KL Lu H Stone B Immunoediting of cancers may lead to epithelial to mesenchymal transition J Immunol 2006 177 3 1526 1533 10.4049/jimmunol.177.3.1526 16849459 38. Santisteban M Reiman JM Asiedu MK Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells Can Res 2009 69 7 2887 2895 10.1158/0008-5472.CAN-08-3343 39. Ward JP Gubin MM Schreiber RD The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer Adv Immunol 2016 130 25 74 10.1016/bs.ai.2016.01.001 26922999 40. Gettinger S Choi J Hastings K Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer Cancer Discov 2017 7 12 1420 1435 10.1158/2159-8290.CD-17-0593 29025772 41. Paulson KG Voillet V McAfee MS Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA Nat Commun 2018 9 1 3868 10.1038/s41467-018-06300-3 30250229 42. Bai J Gao Z Li X Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade Oncotarget 2017 8 66 110693 110707 10.18632/oncotarget.22690 29299180 43. Zaretsky JM Garcia-Diaz A Shin DS Mutations associated with acquired resistance to PD-1 blockade in melanoma N Engl J Med 2016 375 9 819 829 10.1056/NEJMoa1604958 27433843 44. Sade-Feldman M Jiao YJ Chen JH Resistance to checkpoint blockade therapy through inactivation of antigen presentation Nat Commun 2017 8 1 1136 10.1038/s41467-017-01062-w 29070816 45. Tran E Robbins PF Lu YC T-cell transfer therapy targeting mutant KRAS in cancer N Engl J Med 2016 375 23 2255 2262 10.1056/NEJMoa1609279 27959684 46. Cabrera CM Jimenez P Cabrera T Total loss of MHC class I in colorectal tumors can be explained by two molecular pathways: beta2-microglobulin inactivation in MSI-positive tumors and LMP7/TAP2 downregulation in MSI-negative tumors Tissue Antigens 2003 61 3 211 219 10.1034/j.1399-0039.2003.00020.x 12694570 47. Platanias LC Mechanisms of type-I- and type-II-interferon-mediated signalling Nat Rev Immunol 2005 5 5 375 386 10.1038/nri1604 15864272 48. Shin DS Zaretsky JM Escuin-Ordinas H Primary resistance to PD-1 blockade mediated by JAK1/2 mutations Cancer Discov 2017 7 2 188 201 10.1158/2159-8290.CD-16-1223 27903500 49. Fares CM Van Allen EM Drake CG Mechanisms of resistance to immune checkpoint blockade: why does checkpoint inhibitor immunotherapy not work for all patients? Am Soc Clin Oncol Educ Book 2019 39 147 164 10.1200/EDBK_240837 31099674 50. Pardoll DM The blockade of immune checkpoints in cancer immunotherapy Nat Rev Cancer 2012 12 4 252 264 10.1038/nrc3239 22437870 51. Lee JH Shklovskaya E Lim SY Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition Nat Commun 2020 11 1 1897 10.1038/s41467-020-15726-7 32312968 52. Sucker A Zhao F Pieper N Acquired IFNgamma resistance impairs anti-tumor immunity and gives rise to T-cell-resistant melanoma lesions Nat Commun 2017 8 15440 10.1038/ncomms15440 28561041 53. Thommen D Uhlenbrock F Herzig P 66P Highly exhausted PD-1hi T cell subsets in human NSCLC are co-defined by the predominant expression of distinct inhibitory receptors and correlate with clinical outcome J Thorac Oncol 2016 11 4 Supplement S83 10.1016/S1556-0864(16)30179-4 54. Koyama S Akbay EA Li YY Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints Nat Commun 2016 7 10501 10.1038/ncomms10501 26883990 55. Limagne E Richard C Thibaudin M Tim-3/galectin-9 pathway and mMDSC control primary and secondary resistances to PD-1 blockade in lung cancer patients Oncoimmunology 2019 8 4 e1564505 10.1080/2162402X.2018.1564505 30906658 56. Gao J Ward JF Pettaway CA VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer Nat Med 2017 23 5 551 555 10.1038/nm.4308 28346412 57. Kakavand H Jackett LA Menzies AM Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients Mod Pathol 2017 30 12 1666 1676 10.1038/modpathol.2017.89 28776578 58. Fourcade J Sun Z Chauvin JM CD226 opposes TIGIT to disrupt Tregs in melanoma JCI Insight. 2018 3 14 e121157 10.1172/jci.insight.121157 30046006 59. Chiu DK Yuen VW Cheu JW Hepatocellular carcinoma cells up-regulate PVRL1, stabilizing PVR and inhibiting the cytotoxic T-cell response via TIGIT to mediate tumor resistance to PD1 inhibitors in mice Gastroenterology 2020 159 2 609 623 10.1053/j.gastro.2020.03.074 32275969 60. Wu T Dai Y Tumor microenvironment and therapeutic response Cancer Lett 2017 387 61 68 10.1016/j.canlet.2016.01.043 26845449 61. Hanahan D Coussens LM Accessories to the crime: functions of cells recruited to the tumor microenvironment Cancer Cell 2012 21 3 309 322 10.1016/j.ccr.2012.02.022 22439926 62. Wang Q Wu X Primary and acquired resistance to PD-1/PD-L1 blockade in cancer treatment Int Immunopharmacol 2017 46 210 219 10.1016/j.intimp.2017.03.015 28324831 63. Li M Eckl J Geiger C A novel and effective method to generate human porcine-specific regulatory T cells with high expression of IL-10, TGF-beta1 and IL-35 Sci Rep 2017 7 1 3974 10.1038/s41598-017-04322-3 28638110 64. Josefowicz SZ Lu LF Rudensky AY Regulatory T cells: mechanisms of differentiation and function Annu Rev Immunol 2012 30 531 564 10.1146/annurev.immunol.25.022106.141623 22224781 65. Viehl CT Moore TT Liyanage UK Depletion of CD4+CD25+ regulatory T cells promotes a tumor-specific immune response in pancreas cancer-bearing mice Ann Surg Oncol 2006 13 9 1252 1258 10.1245/s10434-006-9015-y 16952047 66. Dyck L Wilk MM Raverdeau M Anti-PD-1 inhibits Foxp3(+) Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model Cancer Immunol Immunother 2016 65 12 1491 1498 10.1007/s00262-016-1906-6 27680570 67. Taylor NA Vick SC Iglesia MD Treg depletion potentiates checkpoint inhibition in claudin-low breast cancer J Clin Investig 2017 127 9 3472 3483 10.1172/JCI90499 28825599 68. Yang L Huang J Ren X Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis Cancer Cell 2008 13 1 23 35 10.1016/j.ccr.2007.12.004 18167337 69. Meyer C Cagnon L Costa-Nunes CM Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab Cancer Immunol Immunother 2014 63 3 247 257 10.1007/s00262-013-1508-5 24357148 70. Arlauckas SP Garris CS Kohler RH In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy Sci Transl Med. 2017 9 389 eaal3604 10.1126/scitranslmed.aal3604 28490665 71. Tie Y Tang F Wei Y-Q Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets J Hematol Oncol 2022 15 1 61 10.1186/s13045-022-01282-8 35585567 72. Salkeni MA Shin JY Gulley JL Naing A Hajjar J Resistance to immunotherapy: mechanisms and means for overcoming Immunotherapy 2021 Cham Springer 45 80 73. Freeman P Mielgo A Cancer-associated fibroblast mediated inhibition of CD8+ cytotoxic T cell accumulation in tumours: mechanisms and therapeutic opportunities Cancers 2020 12 9 2687 10.3390/cancers12092687 32967079 74. Chakravarthy A Khan L Bensler NP TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure Nat Commun 2018 9 1 4692 10.1038/s41467-018-06654-8 30410077 75. Yu L Liu Q Huo J Cancer-associated fibroblasts induce immunotherapy resistance in hepatocellular carcinoma animal model Cell Mol Biol 2020 66 2 36 40 10.14715/cmb/2020.66.2.5 32415924 76. Brochez L Chevolet I Kruse V The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy Eur J Cancer 2017 76 167 182 10.1016/j.ejca.2017.01.011 28324751 77. Eleftheriadis T Pissas G Liakopoulos V IDO decreases glycolysis and glutaminolysis by activating GCN2K, while it increases fatty acid oxidation by activating AhR, thus preserving CD4+ Tcell survival and proliferation Int J Mol Med 2018 42 1 557 568 29693118 78. Labadie BW Bao R Luke JJ Reimagining IDO pathway inhibition in cancer immunotherapy via downstream focus on the tryptophan-kynurenine-aryl hydrocarbon axis Clin Cancer Res 2019 25 5 1462 1471 10.1158/1078-0432.CCR-18-2882 30377198 79. Holmgaard RB Zamarin D Munn DH Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4 J Exp Med 2013 210 7 1389 1402 10.1084/jem.20130066 23752227 80. Wang B Zhao Q Zhang Y Targeting hypoxia in the tumor microenvironment: a potential strategy to improve cancer immunotherapy J Exp Clin Cancer Res 2021 40 1 24 10.1186/s13046-020-01820-7 33422072 81. Gallagher SJ Shklovskaya E Hersey P Epigenetic modulation in cancer immunotherapy Curr Opin Pharmacol 2017 35 48 56 10.1016/j.coph.2017.05.006 28609681 82. Herbst RS Soria J-C Kowanetz M Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients Nature 2014 515 7528 563 567 10.1038/nature14011 25428504 83. Peng D Kryczek I Nagarsheth N Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy Nature 2015 527 7577 249 253 10.1038/nature15520 26503055 84. Ghoneim HE Fan Y Moustaki A De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation Cell 2017 170 1 142 57.e19 10.1016/j.cell.2017.06.007 28648661 85. Pauken KE Sammons MA Odorizzi PM Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade Science 2016 354 6316 1160 1165 10.1126/science.aaf2807 27789795 86. Sen DR Kaminski J Barnitz RA The epigenetic landscape of T cell exhaustion Science 2016 354 6316 1165 1169 10.1126/science.aae0491 27789799 87. Saleh K Khalife-saleh N Kourie HR Is gut microbiome a predictive marker to response to immune checkpoint inhibitors? Immunotherapy 2017 9 11 865 866 10.2217/imt-2017-0090 29251088 88. Burki TK Gut microbiome and immunotherapy response Lancet Oncol 2017 18 12 e717 10.1016/S1470-2045(17)30841-0 29129446 89. Routy B Le Chatelier E Derosa L Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors Science 2018 359 6371 91 97 10.1126/science.aan3706 29097494 90. Gopalakrishnan V Spencer CN Nezi L Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients Science 2018 359 6371 97 103 10.1126/science.aan4236 29097493 91. Matson V Fessler J Bao R The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients Science 2018 359 6371 104 108 10.1126/science.aao3290 29302014 92. Chaput N Lepage P Coutzac C Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab Ann Oncol 2019 30 12 2012 10.1093/annonc/mdz224 31408090 93. Choi J Lee SY Clinical characteristics and treatment of immune-related adverse events of immune checkpoint inhibitors Immune Netw 2020 20 1 e9 10.4110/in.2020.20.e9 32158597 94. Vétizou M Pitt JM Daillère R Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota Science 2015 350 6264 1079 1084 10.1126/science.aad1329 26541610 95. Sahin U Türeci Ö Personalized vaccines for cancer immunotherapy Science 2018 359 6382 1355 1360 10.1126/science.aar7112 29567706 96. Shang S Zhao Y Qian K The role of neoantigens in tumor immunotherapy Biomed Pharmacother 2022 151 113118 10.1016/j.biopha.2022.113118 35623169 97. Verma V Shrimali RK Ahmad S PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1(+)CD38(hi) cells and anti-PD-1 resistance Nat Immunol 2019 20 9 1231 1243 10.1038/s41590-019-0441-y 31358999 98. Ott PA Hu-Lieskovan S Chmielowski B A phase Ib trial of personalized neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer Cell 2020 183 2 347 62.e24 10.1016/j.cell.2020.08.053 33064988 99. Massarelli E William W Johnson F Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: a phase 2 clinical trial JAMA Oncol 2019 5 1 67 73 10.1001/jamaoncol.2018.4051 30267032 100. Guo Z Yuan Y Chen C Durable complete response to neoantigen-loaded dendritic-cell vaccine following anti-PD-1 therapy in metastatic gastric cancer NPJ Precis Oncol 2022 6 1 34 10.1038/s41698-022-00279-3 35661819 101. Ju F Luo Y Lin C Oncolytic virus expressing PD-1 inhibitors activates a collaborative intratumoral immune response to control tumor and synergizes with CTLA-4 or TIM-3 blockade J Immunother Cancer 2022 10 6 e004762 10.1136/jitc-2022-004762 35688558 102. Ribas A Dummer R Puzanov I Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy Cell 2017 170 6 1109 19.e10 10.1016/j.cell.2017.08.027 28886381 103. Chesney J Puzanov I Collichio F Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma J Clin Oncol 2018 36 17 1658 1667 10.1200/JCO.2017.73.7379 28981385 104. Fröhlich A Niebel D Fietz S Talimogene laherparepvec treatment to overcome loco-regional acquired resistance to immune checkpoint blockade in tumor stage IIIB-IV M1c melanoma patients Cancer Immunol Immunother 2020 69 5 759 769 10.1007/s00262-020-02487-x 32052079 105. Roehle K Qiang L Ventre KS cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes Sci Transl Med. 2021 10.1126/scitranslmed.abf5058 34011631 106. Kang SH Keam B Ahn YO Inhibition of MEK with trametinib enhances the efficacy of anti-PD-L1 inhibitor by regulating anti-tumor immunity in head and neck squamous cell carcinoma Oncoimmunology 2019 8 1 e1515057 10.1080/2162402X.2018.1515057 30546955 107. Yamamoto K Venida A Yano J Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I Nature 2020 581 7806 100 105 10.1038/s41586-020-2229-5 32376951 108. Liu C Liu X Xiang X A nanovaccine for antigen self-presentation and immunosuppression reversal as a personalized cancer immunotherapy strategy Nat Nanotechnol 2022 17 5 531 540 10.1038/s41565-022-01098-0 35410368 109. Lei Q Wang D Sun K Resistance mechanisms of anti-PD1/PDL1 therapy in solid tumors Front Cell Dev Biol 2020 8 672 10.3389/fcell.2020.00672 32793604 110. Aznar MA Planelles L Perez-Olivares M Immunotherapeutic effects of intratumoral nanoplexed poly I:C J Immunother Cancer 2019 7 1 116 10.1186/s40425-019-0568-2 31046839 111. Márquez-Rodas I Longo F Rodriguez-Ruiz ME Intratumoral nanoplexed poly I: C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors Sci Transl Med. 2020 10.1126/scitranslmed.abb0391 33055241 112. Kalbasi A Tariveranmoshabad M Hakimi K Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma Sci Transl Med. 2020 10.1126/scitranslmed.abb0152 33055240 113. Motzer RJ Tannir NM McDermott DF Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma N Engl J Med 2018 378 14 1277 1290 10.1056/NEJMoa1712126 29562145 114. Sangro B Chan SL Meyer T Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma J Hepatol 2020 72 2 320 341 10.1016/j.jhep.2019.10.021 31954495 115. Schöffski P Tan DSW Martín M Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies J Immunother Cancer 2022 10 2 e003776 10.1136/jitc-2021-003776 35217575 116. Kondo Y Ohno T Nishii N Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma Oral Oncol 2016 57 54 60 10.1016/j.oraloncology.2016.04.005 27208845 117. Choi J Medikonda R Saleh L Combination checkpoint therapy with anti-PD-1 and anti-BTLA results in a synergistic therapeutic effect against murine glioblastoma Oncoimmunology 2021 10 1 1956142 10.1080/2162402X.2021.1956142 34484870 118. Rodriguez-Abreu D Johnson ML Hussein MA Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE) J Clin Oncol 2020 38 15_suppl 9503 10.1200/JCO.2020.38.15_suppl.9503 119. Arce Vargas F Furness AJS Solomon I Fc-optimized anti-CD25 depletes tumor-infiltrating regulatory T cells and synergizes with PD-1 blockade to eradicate established tumors Immunity 2017 46 4 577 586 10.1016/j.immuni.2017.03.013 28410988 120. Marshall LA Marubayashi S Jorapur A Tumors establish resistance to immunotherapy by regulating T(reg) recruitment via CCR4 J Immunother Cancer 2020 8 2 e000674 10.1136/jitc-2020-000764 32414862 121. Doi T Muro K Ishii H A phase I study of the anti-CC chemokine receptor 4 antibody, mogamulizumab, in combination with nivolumab in patients with advanced or metastatic solid tumors Clin Cancer Res 2019 25 22 6614 6622 10.1158/1078-0432.CCR-19-1090 31455681 122. Zhu Y Yang J Xu D Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade Gut 2019 68 9 1653 1666 10.1136/gutjnl-2019-318419 30902885 123. Shi G Yang Q Zhang Y Modulating the tumor microenvironment via oncolytic viruses and CSF-1R inhibition synergistically enhances anti-PD-1 immunotherapy Mol Ther 2019 27 1 244 260 10.1016/j.ymthe.2018.11.010 30527756 124. Mao Y Eissler N Blanc KL Targeting suppressive myeloid cells potentiates checkpoint inhibitors to control spontaneous neuroblastoma Clin Cancer Res 2016 22 15 3849 3859 10.1158/1078-0432.CCR-15-1912 26957560 125. Li R Salehi-Rad R Crosson W Inhibition of granulocytic myeloid-derived suppressor cells overcomes resistance to immune checkpoint inhibition in LKB1-deficient non-small cell lung cancer Can Res 2021 81 12 3295 3308 10.1158/0008-5472.CAN-20-3564 126. Tobin RP Jordan KR Robinson WA Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab Int Immunopharmacol 2018 63 282 291 10.1016/j.intimp.2018.08.007 30121453 127. Hashimoto A Gao C Mastio J Inhibition of casein kinase 2 disrupts differentiation of myeloid cells in cancer and enhances the efficacy of immunotherapy in mice Can Res 2018 78 19 5644 5655 10.1158/0008-5472.CAN-18-1229 128. Mitchell TC Hamid O Smith DC Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase i results from a multicenter, open-label phase I/II Trial (ECHO-202/KEYNOTE-037) J Clin Oncol 2018 36 32 3223 3230 10.1200/JCO.2018.78.9602 30265610 129. Long GV Dummer R Hamid O Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study Lancet Oncol 2019 20 8 1083 1097 10.1016/S1470-2045(19)30274-8 31221619 130. Sonpavde G Necchi A Gupta S ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer Future Oncol 2020 16 2 4359 4368 10.2217/fon-2019-0611 31823654 131. Lu JC Zhang PF Huang XY Amplification of spatially isolated adenosine pathway by tumor-macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma J Hematol Oncol 2021 14 1 200 10.1186/s13045-021-01207-x 34838121 132. Herbst RS Majem M Barlesi F COAST: An Open-Label, Phase II, Multidrug Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non-Small-Cell Lung Cancer J Clin Oncol 2022 40 3383 10.1200/JCO.22.00227 35452273 133. Chiappori A Williams CC Creelan BC Phase I/II study of the A2AR antagonist NIR178 (PBF-509), an oral immunotherapy, in patients (pts) with advanced NSCLC J Clin Oncol 2018 36 15_suppl 9089 10.1200/JCO.2018.36.15_suppl.9089 134. Mariathasan S Turley SJ Nickles D TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells Nature 2018 554 7693 544 548 10.1038/nature25501 29443960 135. Rivas JR Liu Y Alhakeem SS Interleukin-10 suppression enhances T-cell antitumor immunity and responses to checkpoint blockade in chronic lymphocytic leukemia Leukemia 2021 35 11 3188 3200 10.1038/s41375-021-01217-1 33731852 136. Naing A Wong DJ Infante JR Pegilodecakin combined with pembrolizumab or nivolumab for patients with advanced solid tumours (IVY): a multicentre, multicohort, open-label, phase 1b trial Lancet Oncol 2019 20 11 1544 1555 10.1016/S1470-2045(19)30514-5 31563517 137. Qi Z Xu Z Zhang L Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3Kα/β/δ treatment Nat Commun 2022 13 1 182 10.1038/s41467-021-27833-0 35013322 138. Wang B Liu J Han Y The presence of tertiary lymphoid structures provides new insight into the clinicopathological features and prognosis of patients with breast cancer Front Immunol 2022 13 868155 10.3389/fimmu.2022.868155 35664009 139. Topper MJ Vaz M Marrone KA The emerging role of epigenetic therapeutics in immuno-oncology Nat Rev Clin Oncol 2020 17 2 75 90 10.1038/s41571-019-0266-5 31548600 140. Yi M Zheng X Niu M Combination strategies with PD-1/PD-L1 blockade: current advances and future directions Mol Cancer 2022 21 1 28 10.1186/s12943-021-01489-2 35062949 141. Feng S De Carvalho DD Clinical advances in targeting epigenetics for cancer therapy FEBS J 2022 289 5 1214 1239 10.1111/febs.15750 33545740 142. Wang L Amoozgar Z Huang J Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model Cancer Immunol Res 2015 3 9 1030 1041 10.1158/2326-6066.CIR-15-0073 26056145 143. Woods DM Sodré AL Villagra A HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade Cancer Immunol Res 2015 3 12 1375 1385 10.1158/2326-6066.CIR-15-0077-T 26297712 144. Zheng H Zhao W Yan C HDAC Inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma Clin Cancer Res 2016 22 16 4119 4132 10.1158/1078-0432.CCR-15-2584 26964571 145. Bissonnette RP Cesario RM Goodenow B The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors BMC Cancer 2021 21 1 969 10.1186/s12885-021-08702-x 34461854 146. Zingg D Arenas-Ramirez N Sahin D The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy Cell Rep 2017 20 4 854 867 10.1016/j.celrep.2017.07.007 28746871 147. Morel KL Sheahan AV Burkhart DL EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer Nat Cancer 2021 2 4 444 456 10.1038/s43018-021-00185-w 33899001 148. Daver N Garcia-Manero G Basu S Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a nonrandomized, open-label, Phase II Study Cancer Discov 2019 9 3 370 383 10.1158/2159-8290.CD-18-0774 30409776 149. Gray JE Saltos A Tanvetyanon T Phase I/Ib study of pembrolizumab plus vorinostat in advanced/metastatic non-small cell lung cancer Clin Cancer Res 2019 25 22 6623 6632 10.1158/1078-0432.CCR-19-1305 31409616 150. Entinostat Helps Thwart Immunotherapy Resistance. Cancer discovery. 2019;9(6):685-6 151. Hellmann MD Jänne PA Opyrchal M Entinostat plus pembrolizumab in patients with metastatic NSCLC previously treated with Anti-PD-(L)1 therapy Clin Cancer Res 2021 27 4 1019 1028 10.1158/1078-0432.CCR-20-3305 33203644 152. Elkrief A Derosa L Zitvogel L The intimate relationship between gut microbiota and cancer immunotherapy Gut microbes 2019 10 3 424 428 10.1080/19490976.2018.1527167 30339501 153. Sivan A Corrales L Hubert N Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy Science 2015 350 6264 1084 1089 10.1126/science.aac4255 26541606 154. Mager LF Burkhard R Pett N Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy Science 2020 369 6510 1481 1489 10.1126/science.abc3421 32792462 155. McHale D Francisco-Anderson L Sandy P P-325 Oral delivery of a single microbial strain, EDP1503, induces anti-tumor responses via gut-mediated activation of both innate and adaptive immunity Ann Oncol 2020 31 S195 10.1016/j.annonc.2020.04.407 156. Pant S Mulder I Shah AY A phase I/II study of live biotherapeutic MRx0518 in combination with pembrolizumab in patients who have progressed on prior anti-PD-1 therapy J Clinic Oncol. 2019 37 15 TPS2670 10.1200/JCO.2019.37.15_suppl.TPS2670 157. Baruch EN Youngster I Ben-Betzalel G Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients Science 2021 371 6529 602 609 10.1126/science.abb5920 33303685 158. Davar D Dzutsev AK McCulloch JA Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients Science 2021 371 6529 595 602 10.1126/science.abf3363 33542131 159. Nakamura T Sato T Endo R STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation J Immunother Cancer 2021 9 7 e002852 10.1136/jitc-2021-002852 34215690 160. Li X Khorsandi S Wang Y Cancer immunotherapy based on image-guided STING activation by nucleotide nanocomplex-decorated ultrasound microbubbles Nat Nanotechnol 2022 17 8 891 899 10.1038/s41565-022-01134-z 35637356 161. Buss CG Bhatia SN Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics Proc Natl Acad Sci U S A 2020 117 24 13428 13436 10.1073/pnas.2001569117 32493746 162. Clinical Trials.gov. Available from: https://clinicaltrials.gov/. Accessed May 6 2023. 163. Sahin U Oehm P Derhovanessian E An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma Nature 2020 585 7823 107 112 10.1038/s41586-020-2537-9 32728218 164. Xie C You X Zhang H A nanovaccine based on adjuvant peptide FK-13 and l-phenylalanine poly(ester amide) enhances CD8(+) t cell-mediated antitumor immunity Adv Sci 2023 10.1002/advs.202300418