
==== Front
iScience
iScience
iScience
2589-0042
Elsevier

S2589-0042(24)01975-8
10.1016/j.isci.2024.110750
110750
Review
Innate immune cells in tumor microenvironment: A new frontier in cancer immunotherapy
Li Changhui 12
Yu Xinyu 12
Han Xinyan 12
Lian Chen 1
Wang Zijin 12
Shao Shiqun 3
Shao Fangwei 4
Wang Hua 5
Ma Shenglin mashenglin@medmail.com.cn
6∗
Liu Jian jianl@intl.zju.edu.cn
12789∗∗
1 Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, and Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310029, China
2 Edinburgh Medical School: Biomedical Sciences, College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK
3 Zhejiang Key Laboratory of Smart Biomaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310058, China
4 National Key Laboratory of Biobased Transportation Fuel Technology, ZJU-UIUC Institute, Zhejiang University, Hangzhou 310027, China
5 Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
6 Department of Thoracic Oncology, Hangzhou Cancer Hospital, Hangzhou 310002, China
7 Biomedical and Heath Translational Research Center of Zhejiang Province, Haining, China
8 Cancer Center, Zhejiang University, Hangzhou 310058, China
9 Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou 310058, China
∗ Corresponding author mashenglin@medmail.com.cn
∗∗ Corresponding author jianl@intl.zju.edu.cn
17 8 2024
20 9 2024
17 8 2024
27 9 110750© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Summary

Innate immune cells, crucial in resisting infections and initiating adaptive immunity, play diverse and significant roles in tumor development. These cells, including macrophages, granulocytes, dendritic cells (DCs), innate lymphoid cells, and innate-like T cells, are pivotal in the tumor microenvironment (TME). Innate immune cells are crucial components of the TME, based on which various immunotherapy strategies have been explored. Immunotherapy strategies, such as novel immune checkpoint inhibitors, STING/CD40 agonists, macrophage-based surface backpack anchoring, ex vivo polarization approaches, DC-based tumor vaccines, and CAR-engineered innate immune cells, aim to enhance their anti-tumor potential and counteract cancer-induced immunosuppression. The proximity of innate immune cells to tumor cells in the TME also makes them excellent drug carriers. In this review, we will first provide a systematic overview of innate immune cells within the TME and then discuss innate cell-based therapeutic strategies. Furthermore, the research obstacles and perspectives within the field will also be addressed.

Graphical abstract

Microenvironment; Immune response; Cancer

Subject areas

Microenvironment
Immune response
Cancer
==== Body
pmcIntroduction

Innate immune cells are the first line of host defense against external pathogens and infections. Recently, innate immune cells in the tumor microenvironment (TME) such as macrophages, dendritic cells (DCs), granulocytes, myeloid-derived suppressor cells (MDSCs), innate lymphoid cells (ILCs), and innate-like T cells (ILTCs) have become a research focus in tumor immunity. These cells are now recognized as critical components of the TME, contributing to its heterogeneity and plasticity. The TME is a highly dynamic and complex ecosystem, comprising all non-cancer cells (including fibroblasts, stromal cells, adaptive immune cells, and innate immune cells, etc.) and non-cellular components (including the extracellular matrix (ECM), signaling molecules, blood vessels, etc.).1 Innate immune cells in the TME are highly heterogeneous, with both anti-tumor and pro-tumor functions. Innate immune cells primarily inhibit tumor growth through the nonspecific killing of tumor cells or by invigorating adaptive immune responses.2 However, in the TME, tumor cells, tumor-associated immune cells, and cytokines can change the phenotype of innate immune cells, suppressing their anti-tumor abilities or converting them to a pro-tumor phenotype. Pro-tumor innate immune cells accelerate the progression of tumor cells by directly acting on the tumor cells, inhibiting immune responses, promoting immune evasion, etc.

Over the past two decades, significant advances in adaptive immune cell-based cancer immunotherapy have positioned it as the fourth mainstream cancer treatment after surgery, chemotherapy, and radiotherapy.3 Among these, immune checkpoint inhibitors (ICIs) and adoptive cell therapies (ACTs) have been widely applied in the clinical setting.4,5 These therapies primarily target T cells to harness adaptive immunity’s anti-tumor capabilities. However, T cell-based immunotherapies face limitations, as eliminating heterogeneous cancer cells through specific killing is challenging. Cancer is a heterogeneous disease, and under the selective pressure of adaptive immunity, tumor subclones with weaker immunogenicity become the main subclones that evade immune-mediated tumor clearance. Therefore, innate immune cells, with their nonspecific killing capabilities, are being developed as targets for tumor immunotherapy. Given the heterogeneity of innate immune cells in the TME, one common strategy is to stimulate their anti-tumor abilities, as exemplified by the development of novel ICIs, STING/CD40 agonists, macrophage-based surface backpack anchoring and ex vivo polarization, and DC-based tumor vaccines. Additionally, since innate immune cells are naturally recruited to the TME, they have also been engineered to serve as carriers for anti-tumor drugs to enhance the accumulation of drugs in tumors. Furthermore, CAR-expressing innate immune cells such as macrophages, neutrophils, and natural killer (NK) cells are being actively pursued to improve the tumor-targeting and killing abilities of innate immune cells.

In this review, we systematically explore the various types of innate immune cells, delving into their cellular characteristics, origins, or subgroup classifications and further elucidating their unique contributions and effectiveness in influencing tumor progression within the complex landscape of the TME. Furthermore, from the perspective of clinical treatments, we highlight the significant advantages and potential of innate-immunity-based tumor therapies compared to traditional tumor immunotherapies. This underlines the necessity of continued exploration into the multifaceted roles of innate immune cells within the TME and a reassessment of their significance in this context. Lastly, we will discuss the research bottlenecks and perspectives within the field, aiming to develop strategies to overcome the current limitations of immunotherapy.

Macrophages

Macrophages, vital for innate immunity, contribute to tissue stability, organ development, wound healing, and regeneration. Initially categorized into pro-inflammatory M1 and anti-inflammatory M2 types based on function and metabolism,6,7 further research reveals their extensive diversity and adaptability.8 Macrophages respond dynamically to environmental stimuli, leading to a spectrum of activation states beyond M1/M2 classifications, now expanded to include M1, M2a, M2b, M2c, and M2d subtypes.9 Besides their traditional classification, macrophages function as antigen-presenting cells (APCs) and produce various cytokines to orchestrate adaptive immune responses. For example, macrophages can sample, process, and present antigens via major histocompatibility complex class I/II (MHC I/II) to prime antigen-specific CD8+ and CD4+ T cells.10 It was also reported that pro-inflammatory M1 macrophages can cross-present antigens to prime naive CD8+ T cells and activate memory CD8+ T cells.11 During chronic infection, M1 macrophages reactivate effector CD8+ T cells and produce IL-12 and IL-23, targeting and eliminating infected or malignant cells.12 Furthermore, macrophages secrete a variety of cytokines, which play pivotal roles in activating and modulating T cell responses.13 For example, chemokines secreted by M1 macrophages such as CCL2 (MCP-1), CCL5 (RANTES), and CXCL10 (IP-10) can facilitate the recruitment of NK cells and Th1 cells. The pro-inflammatory cytokines produced by M1 macrophages, including tumor necrosis factor (TNF), IL-1β, IL-6, IL-12, and IL-23, can drive the differentiation of naive T cells into Th1 cells. Additionally, M1 macrophages are instrumental in pathogen and tumor eradication by generating reactive oxygen species (ROS) and reactive nitrogen species (RNS) and by producing inducible nitric oxide synthase (iNOS), which catalyzes the metabolism of arginine into nitric oxide and citrulline.13 Conversely, M2 macrophages express chemokines like CCL17, CCL22, CCL24, CCL26, CCL11, CCL2, and CCL5, supporting Th2 cell proliferation. Moreover, M2 macrophages secrete immunosuppressive cytokines like IL-10 and TGF-β to facilitate Th2 and regulatory T cell (Treg) development.13

In the TME, tumour-associated macrophages (TAMs) are mainly M2 macrophages, with a small portion of M1 macrophages. They are closely associated with tumor initiation, progression, angiogenesis, and metastasis.14 However, the heterogeneity of macrophage is amplified within the TME. The “M1-M2” dichotomy of macrophages is overly simplistic and cannot adequately describe the complex roles of TAMs. For example, TAMs exhibit both M1 and M2 traits in early lung cancer, diffuse-type gastric cancer, and prostate cancer.15 Therefore, better understanding the heterogeneity of TAMs in the TME and their roles in immunotherapy is crucial for exploring innovative immunotherapy strategies.

Within the TME, TAMs are the predominant immune cells, exhibiting heterogeneity with functions ranging from anti-tumor to pro-tumor activities. Anti-tumor TAMs, activated by cytokines like IFN-γ, TNF-α, or granulocyte-macrophage colony-stimulating factor (GM-CSF), promote Type 1 T helper (Th1) responses, express specific surface proteins (CD68, CD80, and CD86), and secrete pro-inflammatory molecules to combat tumors.16 Conversely, pro-tumour TAMs, stimulated by IL-10 or TGF-β, foster Th2 responses, express different protein markers (CD163, CD204, and CD206), and produce anti-inflammatory cytokines, contributing to tumor growth.17 Notably, the crosstalk between pro-tumor TAMs and cancer cells greatly influences tumor malignancy, metastasis, immune evasion, and TAM polarization. For example, in colorectal cancer (CRC), TAMs highly express the CD155 molecule, present an immune-suppressive phenotype, and promote the invasion and progression of cancer cells. Subsequently, these cancer cells secrete IL-4, encouraging macrophages to express CD155, forming a positive feedback loop that accelerates tumor progression.18 Similarly, a comparable feedback loop in triple-negative breast cancer (TNBC) also contributes to cancer promotion.19 Moreover, immune regulatory proteins are indispensable in coordinating TAM polarization and their cancer-promoting activities within the TME. For example, forkhead box protein M1 (FoxM1), as an essential indicator of poor prognosis in cancer patients, can directly upregulate the expression levels of IL1A/1B, vascular endothelial growth factor A (VEGFA), and IL6 after being phosphorylated by mitotic kinase PLK1, thereby recruiting monocytes and inducing the formation of pro-tumor TAMs, promoting immune escape and metastasis of lung adenocarcinoma (LUAD).20 Monocarboxylate transporter 1 (MCT-1) can induce TAMs to secrete IL-6, promoting the polarization of THP-1 monocytes into pro-tumor TAMs, thereby increasing the malignancy of TNBC cells.21 In addition, in cervical cancer, it was observed that cancer cells could induce the production of pro-tumor TAMs by highly expressing TIE2 protein (promoting angiogenesis and balancing the vascular microenvironment) through their exosomes, accelerating vascular generation in the TME.22 These studies demonstrate the role of the TME in directing macrophages toward a pro-tumor phenotype (Figure 1).Figure 1 Pro-tumoural roles of innate immune cells within the tumor microenvironment

Macrophages: Pro-tumour TAMs exhibit high expression of specific surface proteins, facilitating tumor progression. Concurrently, tumor cells secrete IL-4, promoting the expression of these surface proteins by macrophages, thus establishing a positive feedback loop. Immune regulatory proteins expressed by cancer cells (such as TIE2, FoxM1, and MCT-1) can induce the formation of pro-tumour TAMs, further enhancing tumor progression. DCs: The sGSN competes with the cDC1 surface receptor DNGR-1 for binding to F-actin exposed to dead cancer cells, inhibiting the cross-presentation of related antigens and impairing the anti-tumor function of cDC1. Similarly, tumor-derived PGE2 operates through a similar mechanism. Tregs can suppress the cross-presentation of antigens by cDC1 and cDC2, promoting tumor progression. Tumor-derived lactic acid, by affecting the amino acid metabolism of pDCs, encourages the production of Tregs while also reducing the expression of IFN-α in pDCs, rendering them an immunosuppressive phenotype. moDCs similarly exhibit pro-tumoral functions in certain tumor types. Neutrophils: Cancer cells interact with neutrophils in various ways, rendering them an immunosuppressive phenotype and inducing the formation of NETs. This interaction allows neutrophils to promote tumor deterioration through the secretion of oxidants, growth factors, Cathepsin G, and NETs. MDSCs: MDSCs can indirectly promote tumor progression by inhibiting T cell activity or fostering the generation of Tregs. Additionally, interactions between MDSCs and cancer cells can directly enhance tumor progression. ILCs: LTi, ILC2s in hypoxic TME, and ILC3s in specific tumor types exhibit pro-tumoural phenotypes. NKs: The TME can suppress NK cell function through alterations in the surface topography, mitochondrial fragmentation, and the absence of ligands for activating receptors, thus facilitating tumor immune evasion. Abbreviations: TME, Tumor Microenvironment; TAMs, tumour-associated macrophages; IL-4, interleukin-4; TIE2, TEK receptor tyrosine kinase; FoxM1, forkhead box protein M1; MCT-1, monocarboxylate transporter 1; DCs, dendritic cells; sGSN, secretory gelsolin; PGE2, prostaglandin E2; Tregs, regulatory T cells; pDCs, plasmacytoid dendritic Cells; IFN-α, interferon Alpha; moDCs, monocyte-derived dendritic cells; NETs, neutrophil extracellular traps; MDSCs, myeloid-derived suppressor cells; ILCs, innate lymphoid cells; LTi, lymphoid tissue-inducer; NKs, natural killer cells.

Intriguingly, under the complex influences of the TME, TAMs can transition into states with anti-tumor functions. For example, research indicates that CD4+ T cells activated by specific tumor antigens can induce macrophages to adopt anti-tumor characteristics in vitro conditions through interaction with MHC II on pro-tumor TAMs. This process could potentially transform the immune-suppressive TME.23 D-lactic acid, an intestinal microbe metabolite, and the endogenous immune regulator can transform pro-tumor TAMs to anti-tumor macrophages by regulating the phosphatidylinositol 3-kinase/protein kinase B pathway, hindering the progression of hepatocellular carcinoma (HCC).24 Additionally, the transcription factor STAT3, known to be overactivated in various cancers, can be targeted and inhibited by miR-506, a microRNA, altering the polarization of macrophages and encouraging the transition from cancer-promoting pro-tumor TAMs to anti-tumor macrophages.25,26 STING, as a cytoplasmic DNA sensor in the endoplasmic reticulum, decreases endoplasmic reticulum STING content through either its knockdown or activation pathways, which can induce TAM reprogramming to the anti-tumor macrophages, thereby inhibiting the deterioration of gastric cancer cells (Figure 2).27 These findings underscore reprogramming pro-tumor TAMs into anti-tumor macrophages is a promising therapeutic approach.Figure 2 Anti-tumoural roles of innate immune cells within the tumor microenvironment

Macrophages: The polarization of pro-tumor TAMs toward anti-tumor TAMs, which exert anti-tumor functions, can be induced by several factors, including T cells, D-lactate, the suppressed transcription factor STAT3, and a decrease in the endoplasmic reticulum content of STING. DCs: cDC1 competes with tumor cells for glutamate uptake through the amino acid transporter SLC38A2, playing an anti-tumor role. Both cDC1 and cDC2 stimulate the anti-tumor response of T cells through the presentation of tumor antigens. Notably, cDC1 can also induce anti-tumor responses in cDC2. pDCs inhibit tumor progression by expressing IFN-α. However, the anti-tumor potential of moDCs within the TME remains controversial. Neutrophils possess innate cytotoxicity and can exhibit anti-tumor functions by expressing H2O2 and ELANE. ELANE induces apoptosis in cancer cells by hydrolyzing the death domain of CD95 on cancer cells. Additionally, when cancer cells absorb, ELANE can enhance antigen presentation and activate T cells. Innate lymphoid cells: ILC1 and ILC2 can exert anti-tumor effects by expressing relevant factors. Interestingly, ILC3 can limit tumor deterioration by regulating adaptive immune cells and possesses the plasticity to convert into ILC1 for anti-tumor activity. NKs: NKs form synapses with cancer cells and release lytic granules containing perforin and granzymes to activate apoptosis pathways in cancer cells. Similarly, by expressing death receptor ligands (FASL and TRAIL) and binding to death receptors on cancer cells, NKs induce tumor apoptosis. Moreover, NK cells recruit and regulate other immune cells to exert anti-tumor effects by secretion of cytokines, chemokines, and growth factors. Abbreviations: TME, tumor microenvironment; TAMs, tumour-associated macrophages; STAT3, signal transducer and activator of transcription 3; STING, stimulator of interferon genes; DCs, dendritic cells; cDC1, conventional dendritic cell 1; pDCs, plasmacytoid dendritic cells; IFN-α, interferon Alpha; moDCs, monocyte-derived dendritic cells; H2O2, hydrogen peroxide; ELANE, neutrophil elastase; ILCs, innate lymphoid cells; ILC1, innate lymphoid cell type 1; NKs, natural killer cells; FASL, Fas ligand; TRAIL, TNF-related apoptosis-inducing ligand.

Notably, due to the high infiltration of TAMs often associated with poor prognosis in a range of cancers, targeting or eliminating immunosuppressive TAMs can effectively weaken the immune evasion mechanisms of tumors and enhance anti-tumor efficacy. For instance, CD47 (a ubiquitous protein) inhibits the phagocytosis of tumors by macrophages through its interaction with SIRPα (expressed on macrophages). Anti-CD47 antibodies block this interaction, restoring the phagocytic function of macrophages and thereby inhibiting tumor growth and spread. One such anti-CD47 antibody, Hu5F9-G4, has shown promising results in preclinical studies of human acute myeloid leukemia (AML) 41 and pediatric brain tumors.28 Interestingly, utilizing CAR-T cells to eliminate TAMs are also a promising potential therapy. Recent studies have designed CAR-T cells targeting macrophage markers such as F4/80 and folate receptor β, effectively eliminating TAMs in mouse tumor models and enhancing anti-tumor immunity.29,30 Moreover, a recent study has highlighted the critical role of TAMs in the dysfunction of mucosal-associated invariant T (MAIT) cells within hepatocellular carcinoma (HCC). By targeting the interaction between TAMs and MAIT cells, particularly the CSF1R+PD-L1+ TAMs, it is possible to reinvigorate the anti-tumor function of MAIT cells.31

Dendritic cells

DCs, critical APCs, bridge innate and adaptive immunity by recognizing tumors and invaders like pathogens and viruses through the membrane or cytoplasmic receptors. They uptake and present non-self-antigens to naive T cells via MHC molecules, stimulating adaptive immune responses. Like macrophages, DCs are heterogeneous and include conventional dendritic cells (cDCs, subtypes cDC1 and cDC2), plasmacytoid dendritic cells (pDCs), and monocyte-derived dendritic cells (moDCs). These classifications are based on tissue localization, phenotypic characteristics, and function. Functionally, cDC1 excels in cross-presenting antigens, which is crucial for processing endogenous and exogenous antigens. It presents tumor and pathogen antigens on MHC I molecules to CD8 T cells, activating anti-tumor and anti-pathogen responses.32 Conversely, cDC2, with limited cross-presentation capacity, targets exogenous antigens to CD4 T cell subsets (Th1, Th2, and Th17) via MHC II, crucial for responding to extracellular pathogens.33 In addition, pDCs produce significant type I interferon (IFN-ǀ/α) upon Toll-like receptor (TLR) stimulation, contributing to anti-pathogen and anti-tumor immunity.34 However, within the TME, the response-ability of pDCs to TLR7/9 activation decreases, impairing IFN-α production and fostering an immunosuppressive environment.34 Unlike cDCs and pDCs, moDCs are typically not observed under normal conditions but appear in response to inflammation, cancer, or infection. This link to specific conditions leads to their alternative name, inflammatory DCs (inf-DCs).35

Immune-tolerant DCs can promote tumor immune evasion and subsequent progression. In the TME, soluble molecules and immunosuppressive factors induce an immune-tolerant phenotype in DCs by regulating transcription and metabolic pathways. For instance, secretory gelsolin (sGSN), as an extracellular protein in animal plasma, can compete with the DNGR-1 surface receptor of cDC1 for F-actin exposed by dead cancer cells, hindering the cross-presentation of dead cell-related antigens dependent on DNGR-1, and damaging the anti-tumor function of cDC1.36 Moreover, tumor-derived prostaglandin E2 (PGE2), as an immune regulatory factor, upregulates the cAMP signal transduction of cDC1 through its receptors, prostaglandin E2 (EP2) and EP4, diminishing the key cDC1 differentiation factor IRF8 and impairing cDC1 function in tumors.37 Tregs have immunosuppressive characteristics, and local Treg-DC interactions in the TME are crucial for their immunosuppressive functions. For example, INF-γ, as an immune regulatory factor, increases its expression in the tumor-draining mediastinal lymph nodes (mLN), prompting Treg cells to polarize into TH1-like effector Treg cells, driving them to suppress cDC1 in a spatially coordinated manner, making it unable to induce anti-tumor responses.38 IFN can also increase the chemokine CXCL9, which is crucial for coordinating immune cells in the TME.39 The chemokine receptor CXCR3 is expressed on Treg cells, and activated CXCR3+ Treg cells tend to crosstalk with BATF3+ cDC1, which can express CXCL9, thereby inhibiting the cross-presentation of tumor antigen by cDC1 and promoting tumor progression.40 Despite the predominance of cDC2 in the TME, studies have mainly focused on the cross-presentation of antigens by cDC1, neglecting the tumor-promoting potential of cDC2 due to its lack of distinct membrane markers for identification. However, the significance of cDC2 within the TME should not be overlooked. Similarly to cDC1, the interaction of cDC2 with Treg cells contributes to tumor progression. In the TME of hypoxic HCC, the interplay between Treg cells and cDC2 leads to the loss of the antigen-presenting molecule, human leukocyte antigen-DR isotype (HLA-DR), on cDC2. This loss hinders the activation of T cell anti-tumor functions, promoting an immunosuppressive TME.41 Similarly, tumor metabolic product lactic acid enhances the tryptophan metabolism and kynurenine expression of pDCs, stimulating the production of immunosuppressive FoxP3+ CD4+ Treg cells. pDCs affected by lactic acid can also undergo pro-tumor reprogramming, causing their IFN-α expression to decrease and presenting an immunosuppressive phenotype.42 In addition, numerous studies confirm that pDCs usually present an immune-tolerant phenotype and play a pro-tumor role in the TME.43,44,45 moDCs, when influenced by the TME, display an immunosuppressive phenotype, leading to tumor malignancy. This has been observed within ovarian cancer, chronic granulocytic leukemia, and chronic lymphocytic leukemia (Figure 1).46,47,48

Immune-activated DCs can promote tumor immune clearance and subsequent suppression. The cDC1 subgroup presents tumor antigens to CD8+ T cells via MHC I, aiming to elicit CTL-guided responses.49 Research has found that in LUAD, cDC1 maintains the TCF-1+ CD8+ T cell reserve in the tumor-draining lymph nodes (dLN), exerting anti-tumor functions.50 Meanwhile, tumor progression correlates with a reduction in cDC1 numbers and functional impairments.50 It is worth noting that the gene-edited mouse model with Xcr1 defects highlights the significant anti-tumor capabilities of cDC1, exceeding current understanding.51 This study reveals the crucial role of cDC1 in initiating the anti-tumor response of cDC2 beyond its known cross-presentation activity.51 In addition to cross-presentation, the co-stimulatory ligands and nutrients of cDC1 are vital for enhancing anti-tumor immunity and tumor rejection reactions. For example, CD40-dependent cDC1 induces the production of co-stimulatory ligands (CD70, 4-1BB) of CD8+ T cells and Bcl2l1 protein that prevents cell death, safeguarding its anti-tumor immunity.52 In addition, recent studies identify nutrients like glutamine as critical regulators of immune homeostasis, crucial for cDC1 function in the TME.53 cDC1 competes with tumor cells for the uptake of glutamine through the amino acid transporter SLC38A2, influencing anti-tumor immunity.53 In the mouse tumor model supplemented with glutamine in the tumor, tumor growth can be inhibited by enhancing the CD8+ T cell immune response mediated by cDC1.53 Despite its limited capacity compared to cDC1, cDC2 significantly contributes to tumor suppression. For instance, an increase in IL-6 expression in the blood of pancreatic ductal adenocarcinoma (PDAC) patients decreases the number of circulating cDC2s, which is associated with poor prognosis in PDAC patients.54 Additionally, in HPV16-driven oral cancer, CD163+ cDC2 stimulates type 1 T cell polarization, triggering an anti-tumor response.55 The anti-tumor function of pDC primarily operates through IFN-α expression, inhibiting tumor proliferation, metastasis, and angiogenesis.56 For example, studies show OX40+ pDCs, with their immune-stimulating and cytolytic traits, produce IFN-α and collaborate with cDC1 to eradicate head and neck squamous cell carcinomas.57 Additionally, pDCs can collaborate with NK and CD8+ T cells to combat breast cancer.58 Despite the debated role of moDCs in tumors like multiple myeloma (MM), research into their anti-tumor potential in the TME continues (Figure 2).59

Granulocytes

Granulocytes traditionally include neutrophils, eosinophils, and basophils. Although mast cells contain basophilic granules, they do not originate from the common granulocyte precursor, making their classification controversial. However, given that mast cells share functional similarities with traditional granulocytes in the TME, they are also discussed in this section. The heterogeneity of neutrophils in the TME is a significant focus of tumor immunology research and will be discussed in detail. Additionally, the anti-tumor and pro-tumor roles of eosinophils, basophils, and mast cells will be briefly discussed.

Neutrophils

Neutrophils, the most abundant immune cells in human blood, serve as the first line of defense against microbial infections. Previously, due to the short lifespan and non-differentiation of neutrophils, their role in cancer was overlooked. However, neutrophils are now recognized as critical players in the TME, involved in all cancer development stages. Tumor-associated neutrophils (TANs) show phenotypic diversity in their anti-tumor and tumor-promoting roles. In 2009, Fridlender et al. proposed a binary classification of TANs into anti-tumor (“N1”) and tumor-promoting (“N2”) types, mirroring the TAMs classification.60 This classification marked a milestone in TAN research, though recent single-cell analyses suggest it’s an oversimplification, with N1 and N2 representing only the extremes.61,62

The innate cytotoxic ability of neutrophils is crucial to their anti-tumor capabilities. Tumor-entrained neutrophils (TENs) prevent metastatic seeding in the lungs by producing H2O2.63 Neutrophil elastase (ELANE) released by neutrophils can hydrolyze the death domain of CD95 in cancer cells, inducing their apoptosis. At the same time, when ELANE is taken up by breast cancer cells, it can enhance antigen presentation and activate cytotoxic T cells. These anti-tumor effects can be regarded as an extension of the antibacterial effect of neutrophils (Figure 2).64

Multiple aspects of the TME regulate the phenotypic transformation of neutrophils from anti-tumor to pro-tumor. Meng et al. found that cancer cells can secrete nicotinamide phosphoribosyltransferase (NAMPT) to induce CD10+ALPL+ neutrophils in the TME to stay in an immature state and show immunosuppressive ability, inducing CD8+ T cell exhaustion.65 In addition to secreting cytokines, cancer cells can also change the phenotype of neutrophils through direct interaction with neutrophils. In PDAC, cancer cells and neutrophils can form a channel through gap junction protein Beta 3 (GJB3), through which cancer cells transfer cAMP to neutrophils, supporting the survival and polarization of neutrophils.66 In addition, PD-1 expressed by cancer cells can interact with PD-L1 expressed by neutrophils to inhibit the cytotoxicity of neutrophils.67 Non-cancer cells can also regulate the phenotype of neutrophils. Gong et al. found that lung mesenchymal cells can make infiltrating neutrophils show immunosuppressive manifestations, which can strongly inhibit T cells and NK cells, thereby promoting breast cancer metastasis.68 The TME can also drive neutrophils to form neutrophil extracellular traps (NETs), a net-like structure with DNA as the scaffold and loaded with cytotoxic proteins. Recent studies have found that NETs play an essential role in tumor development. The tissue inhibitor of metalloproteinases-1 (TIMP1) secreted by the tumor interacts with CD63 of neutrophils in PDAC, triggering the downstream ERK signaling pathway, thereby inducing the formation of NETs.69 The metabolic transformation induced by tumors enhances the glycolysis and pentose phosphate pathway of neutrophils, which indirectly promotes the production of NETs.70 In addition, fibroblasts in the TME can secrete collagen to activate the membrane receptor DDR1 of cancer cells, thereby upregulating CXCL5 expression. CXCL5 will promote the recruitment of neutrophils and the formation of NETs.71 In addition, TME hypoxia also induces NETs formation (Figure 1).72

Following phenotypic transformation, pro-tumour neutrophils facilitate tumor initiation, development, and metastasis via multiple pathways. During inflammation, oxidants secreted by neutrophils will cause DNA damage to epithelial cells and further lead to cancer initiation.73,74 After cancer initiation, neutrophils can promote the survival and proliferation of tumor cells. Neutrophils can release a series of growth factors, such as platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), etc., promoting cancer cell growth and countering senescence. NETs-DNA can interact with the membrane protein CCDC25 of cancer cells and activate the downstream pathway of cell proliferation.75,76 NET-associated proteins like MMP9 and NE can remodel the ECM, and the matrix protein after enzymatic remodeling can activate tumor cell proliferation signaling pathways.77,78,79 Moreover, neutrophils and the contents related to NETs can secrete pro-angiogenic factors, promoting tumor vasculature formation and nourishing tumor growth.79 When the tumor grows to a particular stage, neutrophils can increase the invasiveness of the primary tumor. Cathepsin G derived from neutrophils can hydrolyze the ECM of cancer cells to increase the flexibility of cancer cells, which is conducive to the occurrence of metastasis.76 In addition, in CRC, NETs have also been found to promote the formation of pseudopodia of cancer cells and their movement.80 When cancer cells enter the circulating blood, NETs released by neutrophils can dilate blood vessels, facilitating cancer cell migration.81 When the NETs in the blood vessels capture the circulating tumor cells, it can enhance the migration ability and stemness of cancer cells, thereby further promoting tumor metastasis.82 In addition, neutrophils have been found to accumulate in the lung pre-metastatic niche.83 On the one hand, the NETs in the pre-metastatic niche can act as a chemokine to recruit cancer cells, and on the other hand, the metastatic cancer cells will enter a dormant state.75 NETs help to activate dormant cancer cells and promote cancer cells to re-enter the cell cycle (Figure 1).78

Eosinophils

Traditionally studied in parasitic infections and allergies, eosinophils also infiltrate various tumors, playing complex roles in the TME.84 Eosinophils in the TME can exhibit both anti-tumor and pro-tumor activities. Under the influence of IL-5, IL-33, CCL11, IFNγ, and TNF, eosinophils secrete cytotoxic proteins (MBP, ECP, EDN, granzymes, etc.) to induce tumor cell death directly.85 Eosinophils can also exert anti-tumor functions by promoting NK cell migration and activation by secreting CCL5, CXCL10, and IL-12 and recruiting CD8+ T cells through secreting IFNγ.84 Conversely, eosinophils can support tumor growth by attracting Treg cells via CCL22 and suppressing effector T cells through 2,3-dioxygenase (IDO)-mediated tryptophan degradation.85 Current research on eosinophil function in cancer and cancer therapy is limited, as eosinophils are often “absent” in most single-cell RNA sequencing analyses, hindering the discovery and identification of eosinophil subsets.84 Future studies are needed to overcome these limitations.

Basophils

Basophils, comprising only 0.5–1% of circulating white blood cells, are vital participants in IgE-mediated responses.86 Basophils infiltrating various human cancers play dual roles in tumor development. Regarding anti-tumor activities, intratumoral basophils secrete CCL3/CCL4, which recruits CD8+ T cells into the TME, indirectly suppressing melanoma in mouse models.87 Additionally, basophils secrete TNFα and granzyme B, which can exert direct cytotoxic effects on tumor cells.86 Conversely, in pro-tumor activities, cancer cells overexpressing galectin-3 (Gal-3) can activate basophils to secrete large amounts of IL-4 and IL-13,88 promoting macrophage polarization toward M2-like macrophages,86 indirectly facilitating cancer progression. Moreover, basophil-derived VEGF-A can enhance angiogenesis and promote tumor growth and metastasis.89

Mast cells

Mast cells also contain basophilic granules in the cytoplasm and have long been associated with the pathogenesis of allergic and autoimmune diseases. Recent studies suggest that as tissue-resident myeloid cells, mast cells can shape the TME through their potent inflammatory mediators, playing either promotive or suppressive roles in tumor progression.90 In terms of anti-tumor activities, mast cells act as sentinel immune cells, releasing chemokines such as CXCL10, CCL3, and CCL5, which recruit CD8+ and CD4+ T cells to the TME, further regulating T cell activity through secreting TNF-α. Depending on the stimulated receptors, histamine released by mast cells can induce specific helper T cell subsets or T cell regulatory responses.90 Activated mast cells have also been shown to upregulate MHC II and co-stimulatory molecules, functioning as local APCs for T cells.90,91 On the pro-tumor side, mast cells can support angiogenesis, inflammation, and homeostasis, promoting cancer development.90,92 Mast cells release proteases like tryptase and chymase, which activate matrix metalloproteinases, degrading ECM and surrounding tissue, thus facilitating tumor growth, angiogenesis, and metastasis.92 Additionally, mast cells secrete VEGF, PDGF-β, and IL-6 to promote angiogenesis, cancer cell proliferation, and tumor growth.90

MDSCs

In recent years, MDSCs have become a significant regulator of immune responses in cancer and other pathological conditions. In advanced cancer stages, a subset of mononuclear phagocytes (MNPs) and granulocytes are commonly characterized by immature morphology, markers, and immunosuppressive functions.93 Fifty years ago, researchers discovered that bone marrow cells could suppress T cell function, leading to their characterization as natural suppressor cells. In the early 2000s, these cells were renamed myeloid suppressor cells (MSCs), associated with immunosuppression in late-stage cancer patients.93,94 In 2007, the term MDSCs was formally proposed to describe immature and heterogeneous myeloid cells within pathological environments.95 However, the initial purpose of introducing this term was not to define a new group of myeloid cells but to provide a term that could summarize the function, origin, and heterogeneity of this group of cells.96 With the development of molecular biology, the definition of MDSCs has been further refined. In mice, MDSCs have consistently been characterized by the simultaneous expression of Gr-1 (anti-Gr-1 monoclonal antibody recognizes common epitopes of Ly6C and Ly6G) and CD11b. Subsequently, based on morphology and molecular biology characteristics, MDSCs were further differentiated into two cell groups: polymorphonuclear-MDSCs (PMN-MDSCs): CD11b+ Ly6G+ Ly6Clow, accounting for more than 75%; mononuclear-MDSCs (M-MDSCs): CD11b+ Ly6G− Ly6Chigh, accounting for about 10%–20%.96 Notably, M-MDSCs have a more vital immunosuppressive ability than PMN-MDSCs. Despite the MDSCs group having heterogeneity and overlap with traditional cell classifications, the significance of MDSCs in clinical and scientific research remains undiminished, underlining the continuous efforts to understand their role, especially within the TME.93

MDSCs are crucial in immune suppression and are significantly linked to poor clinical cancer outcomes. MDSCs can release a variety of substances to enhance the stemness of cancer cells and inhibit T cell activity to promote tumor development. PMN-MDSCs can induce the upregulation of piRNA-823, activate DNA methyltransferases (DNMTs), and enhance the growth and stemness of MM cells. The silencing of piRNA-823 in MM cells reduces the stemness of MM stem cells maintained by PMN-MDSCs, potentially reducing tumor burden and angiogenesis in the body.97 Furthermore, M-MDSCs suppress IL-2 secretion, CD25 expression, and STAT-5 phosphorylation in T cells in a nitric oxide-dependent manner, aiming to inhibit T cell proliferation and activation.98 Moreover, M-MDSCs induce the generation of immunosuppressive Foxp3 Tregs by releasing TGF-β.99 Similarly, MDSCs can also cause the expression miRNA101 in cancer cells. miRNA101 then inhibits the co-repressor gene C-terminal binding protein-2 (CtBP2), leading to the upregulation of stem cell core gene expression, and increased cancer cell stemness, metastasis, and tumorigenic potential.100 In addition, PMN-MDSCs can secrete exosomes containing S100A9 to promote the progression of mouse CRC cells. Under hypoxic conditions in TME, PMN-MDSCs release more exosomes in a dependent manner of a hypoxia-inducible factor 1α (HIF-1α). Clinical data show that human MDSCs enhance the stemness and growth of colorectal cancer cells through exosomal S100A9, with significantly higher levels of exosomal S100A9 in the plasma of colorectal cancer patients compared to healthy subjects.101 Another study shows that MDSCs can promote tumor progression through “suicide”. PMN-MDSCs in the TME will undergo spontaneous death through ferroptosis. Although the presence of PMN-MDSCs is reduced, ferroptosis induces the release of oxygenated lipids. These lipids then inhibit T cell activity, further facilitating tumor progression (Figure 1).

Innate lymphoid cells

ILCs lack adaptive antigen receptors produced through genetic recombination and are the innate counterparts of T lymphocytes, primarily residing in tissues.102,103 ILC1, ILC2, and ILC3 functionally mirror Th1, Th2, and Th17, respectively, while NK cells reflect the function of CD8 cytotoxic T cells. ILCs act in the early immune response, whereas T cell responses take several days due to their clonal expansion process. After several days of immune response, ILCs and T cells can work together and cross-regulate each other. For example, ILCs can express MHC II and present antigens, modulating antigen-specific T cell activity, while interleukin-2 produced by T cells can enhance ILC activity. These cells form a positive feedback loop to amplify the response and inhibit each other by competing for survival factors.103

The terminology for ILCs and ILC subsets 2013 grouped ILCs into three categories based on cytokine production and the transcription factors required for their development and function. Group 1 includes NK cells and ILC1s, which depend on the T-box transcription factor T-bet and produce IFN-γ. Group 2 provides ILC2 cells, which rely on GATA3 and RORα and produce type 2 cytokines, mainly IL-5 and IL-13. Group3 includes ILC3 and lymphoid tissue-inducer (LTi) cells, which depend on the transcription factor RORγt and can produce IL-17 and IL-22.104 With further exploration of ILC heterogeneity and more detailed molecular data on ILC development, the latest classification divides ILCs into five subsets: NK cells, ILC1, ILC2, ILC3, and LTi cells.103 All five subsets of ILCs have been found to play roles in tumor development, with the most extensive research focused on NK cells. In the following texts, we will discuss the role of NK cells in tumor progression in detail and provide a brief overview of the roles of the other four ILC subsets in cancer.

Unlike T cells, which specifically recognize tumor antigens, the cytotoxicity of NK cells is unique and nonspecific. NK cells identify tumor cells based on the “missing self” principle. NK cells possess two types of receptors on their surface: inhibitory and activating. Inhibitory receptors bind to tumor ligands such as MHC I molecules, which show signals of “self” and prevent NK cell activation. Activating receptors, on the other hand, bind to stress-induced ligands on tumor cells, leading to NK cell activation. A balance between signals regulates NK cell activation from activating and inhibitory receptors. When activating signals are present and inhibitory signals are absent or reduced, NK cells become activated and mediate cytotoxicity against the tumor cells.105,106

NK cells primarily inhibit primary tumor growth via apoptosis. Upon recognizing tumor cells, NK cells form synapses, which transport lytic granules from NK cells to tumor cells.107,108,109 Lytic granules contain two main killing molecules: perforin and granzymes. Perforin can be inserted into the target cell’s plasma membrane and form pores, leading to the osmotic lysis of cancer cells. Meanwhile, granzymes enter cancer cells through the pores, activate caspase signaling pathways, and ultimately trigger cancer cell apoptosis.108,109 NK cells can mediate targeted cancer cell apoptosis by expressing death receptor ligands FASL and TRAIL, binding to death receptors on cancer cells.110,111 Beyond apoptosis, NK cells also initiate anti-tumor responses through pyroptosis. For example, NK cells release granzyme A into targeted tumor cells to cleave gasdermin B, releasing its pore-forming activity and mediating cancer cell pyroptosis.112 Apart from their cytotoxicity, NK cells can also exert anti-tumor effects by secreting cytokines (IFN-γ, IL-13, TNF, etc.), chemokines (CCL3, CCL4, CCL5, CXCL1, etc.), and growth factors (FMS-like tyrosine kinase 3 ligand (FLT3L), GM-CSF, etc.). This helps NK cells recruit and regulate other immune cells. For instance, NK cells release FLT3L in the TME to activate DCs and increase T cell activity, triggering anti-tumor immune responses (Figure 2).113

However, tumor cells can escape the surveillance of NK cells by regulating surface ligands. As mentioned before, the recognition of tumor cells is based on the balance between inhibitory and activating ligands presented by cancer cells. Upregulating inhibitory ligands are a theatrical strategy for tumor cells to escape NK surveillance. In most cases, tumor cells reduce MHC I expression to evade T cell-mediated killing. The downregulation of MHC I in melanoma has been shown to be a significant cause of anti-PD-1 immunotherapy resistance.114 However, when NK cells are co-cultured with melanoma cells, the tumor cells upregulate MHC I to escape NK cell surveillance.115 Additionally, downregulating activating ligands is another strategy. NKG2D is an activating receptor that binds to tumor cell NKG2D ligands (NKG2DLs), triggering tumor cell destruction.116 Studies have found that AML stem cells evade NK cell killing by lacking NKG2DL expression.117 In glioblastoma multiforme (GBM), the overexpression of EZH2-92aa encoded by circular EZH2 coding protein inhibits NKG2DLs, inducing GBM stem cells (GSCs) to evade NK cells (Figure 1).116

In addition to suppressed recognition ability, the killing efficiency of NK cells toward cancer cells is also severely affected in the TME. Research has revealed that within the TME, a disruption in serine metabolism precipitates a decline in sphingomyelin (SM) levels in intratumoral NK cells. This metabolic imbalance reduces the number and length of NK cell membrane protrusions, hindering immune synapse formation with HCC cells. This metabolic dysregulation reduces the number and length of cell membrane protrusions, thereby impeding the formation of immune synapses with HCC cells. Consequently, this hampers the cytotoxic capabilities of NK cells.118 Mitochondrial fragmentation induced by the TME in NK cells is also an essential immune escape mechanism. Hypoxic tumor areas enhance the key signal mTOR-Drp for mitochondrial fragmentation and apoptosis of tumor-infiltrating NK cells (TINK). This leads to NK cell loss and weakened cytotoxicity, thereby driving tumor immune escape.119

Research on the role of ILCs in tumor development is less extensive than that on NK cells. As part of group ILCs, ILC1 inhibits the organ metastasis of disseminated cancer cells and shows an anti-tumor phenotype similar to that of NK cells. However, the phenotypes of the other two groups of ILCs exhibit heterogeneity.

Moral et al. reported that ILC2s can infiltrate PDACs to activate tissue-specific tumor immune responses.120 Furthermore, ILC2s can promote lung cancer metastasis by inhibiting NK cells through IL-5-dependent eosinophils.121 However, in highly infiltrated melanomas, ILC2s can coordinate the recruitment and activation of eosinophils by expressing GM-CSF, which enhances anti-tumour immune responses.122 Ye et al. found that in hypoxic TME, ILC2s play an immunosuppressive role in PDACs through reprogramming.123

LTi cells can promote the growth of lymphatic vessels in the TME and coordinate the expression of lymphoid cytokines, leading to tumor metastasis within the lymphatic system.124,125 ILC3s play different functions in various types of tumors. ILC3s in CRC can regulate adaptive immune cells and the intestinal immune environment, limiting tumor deterioration.126 Similarly, in the melanoma TME, tumor-infiltrating ILC3s have been found to have the plasticity to transform into ILC1s, have cytotoxicity in humans and mice, and can inhibit tumor progression in mouse tumor models.127 Preliminary, non-systematic studies have suggested a potential role for ILC3s in accelerating the progression and tissue metastasis of pancreatic cancer, HCC, and breast cancer.124,128,129 However, understanding the functions and impacts of ILC3s in the progression and metastasis of other tumor types remains limited (Figures 1 and 2).

Innate-like T cells

ILTCs, like ILCs, are tissue-resident lymphocytes that can rapidly respond to environmental changes. ILTCs consist of three key subsets: invariant natural killer T (iNKT) cells, MAIT cells, and γδ T cells. These cells have multifunctional capabilities and rapidly respond to non-peptide antigens through their conserved T cell receptors (TCRs).130 iNKT cells possess a semi-invariant TCR composed of an invariant α-chain paired with a limited number of TCR β-chains. This TCR is reactive to both self and foreign glycolipid ligands, including α-galactosylceramide (α-GalCer) presented by the MHC I-like molecule CD1d.131 MAIT cells have a highly restricted TCRα chain paired with a limited set of TCRβ chains and can detect microbial metabolites derived from vitamin B2 (riboflavin) or vitamin B9 (folic acid) presented by MR1.132 γδ T cells express TCRs consisting of γ and δ chains instead of the conventional αβ chains. They can respond rapidly in an innate-like manner, indicating their potential role as first responders in immune responses.130

Although the importance of NK cells in cancer has been known for many years, ILCs and ILTCs have only recently been recognized as significant regulators in cancer immunology. ILTCs can have both pro-tumour and anti-tumor effects, depending on the environment, as the pro-inflammatory cytokines released in the TME induce unique transcriptional profiles in these cells.130 Regarding anti-tumor activity, unlike ILCs, ILTCs can exert direct tumor-killing effects through TCRs. iNKT cells can be activated by the glycolipid ligand α-GalCer to mediate anti-tumor effects in a CD1d-restricted manner both in vitro and in vivo. TCR agonists can activate 166 MAIT cells to reduce tumor burden in lung and liver metastasis models.133 γδ T cells and iNKT cells can recognize tumor cells either through their TCRs or by expressing activating receptors such as NKG2D, NKp30, or NKp44.134 Additionally, ILTCs can lyse cancer cells by releasing granzyme B and perforin or induce tumor cell apoptosis by expressing TRAIL.130 Conversely, regarding pro-tumor effects, chronic secretion of IL-16 by ILTCs and ILCs contributes to tumor initiation and progression.130,135 ILTCs, such as γδ T and MAIT cells, can also secrete TGF-β, promoting tumor immune evasion and poor responses to anti-tumor therapies when perturbed in the TME.136 Moreover, within the TME, ILTCs can be polarized into a tumor-promoting phenotype in a TCR-dependent manner.130

Tumor immunotherapies are based on innate immune cells

Innate immune cells, as crucial components of the TME, can be recruited by tumor cells and possess plastic phenotypes, making them significant targets for cancer therapy. As previously mentioned, innate immune cells within the TME are generally heterogeneous, possessing both anti-tumor and pro-tumor potential. The standard strategy is to stimulate the anti-tumor capabilities of these immune cells or to relieve them from the immunosuppressive effects exerted by tumor cells. Therapies based on this strategy include ICIs, STING/CD40 agonists, macrophage-based surface backpack anchoring and ex vivo polarizing, and DC-based tumor vaccines. Taking advantage of the recruitment and proximity of innate immune cells to cancer cells within the TME, these cells can be transformed into carriers of anti-tumor drugs to enhance the targeting and efficiency of the drugs. Additionally, innate immune cells with CARs can further improve the targeting specificity of immune cells, accurately exerting tumor-killing effects.

Immune checkpoint inhibitors

Currently, ICIs have emerged as a frontline therapeutic strategy for both solid tumors and hematological malignancies, marking a breakthrough in the field of cancer immunotherapy.137 Classic ICIs activate T cells by removing their inhibitory signals, rebuilding anti-tumor responses, and preventing tumor cells from evading immune surveillance. Immunotherapeutic agents, specifically antibodies that inhibit the classical immune checkpoints CTLA-4, PD-1, and its ligand PD-L1, are extensively utilized in the medical field.137 While classic ICIs show some clinical efficacy, primarily targeting T cells, many patients develop primary or acquired resistance, restricting benefits to a small minority.137,138 Furthermore, a practical approach to combat drug resistance involves the alteration of drug targets. This leads to the prospect of developing ICIs that specifically target non-T cells. The initiation, progression, and maintenance of T cell effector functions rely on the innate immune system. Therefore, screening out immune checkpoints that consider innate immune cells as the basis may be instrumental in enhancing the clinical treatment efficacy.

Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin (Ig) and mucin domain-3 (TIM-3), and T cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif (ITIM) domain (TIGIT) are the second wave of immune checkpoints discovered after CTLA-4 and PD-1/L1.139 Following these, NK Group 2A (NKG2A) and signal regulatory protein alpha (SIRPα) were identified as additional immune checkpoints (Figure 3).Figure 3 Immune checkpoint inhibitors based on innate immune cells

(A) Upon binding to its ligand, LAG-3 inhibits anti-tumor responses from CD4+ and CD8+ T cells; it can also activate immunosuppressive responses from Tregs directly or through pDC-mediated pathways. Relatlimab is an antibody targeting LAG-3.

(B) TIM3, an inhibitory immune checkpoint receptor expressed on T cells, DCs, macrophages, and NKs, interacts with ligands such as PtdSer, HMGB1, galectin-9, and CEACAM1, leading to the suppression of anti-tumor responses. Antibodies that block TIM3 include Sym023, INCAGN02390, and sabatolimab.

(C) TIGIT, a receptor found on the surface of T or NK cells, interacts with ligands such as CD112, CD113, CD155, and nectin-4, which are present in tumor cells and APCs. This interaction results in immune suppression and NK cell exhaustion. Antibodies that inhibit TIGIT include vibostolimab, etigilimab, tiragolumab, and ociperlimab.

(D) Expressed in CD8+ T cells and NK cells, NKG2A can form a heterodimer with CD94 and bind to HLA-E on tumor cells, leading to immunosuppression. Monalizumab, an NKG2A-blocking antibody, enhances NK cell degranulation and IFN-γ production, thereby strengthening their anti-tumor activity.

(E) Cancer cells express CD47, which binds to the SIRPα receptor on myeloid cells, conveying a “don’t eat me” signal that inhibits the tumor-killing capacity of myeloid cells. Magroliumab and TTI-621 are antibodies designed to disrupt the SIRPα-CD47 interaction. Abbreviations: LAG-3, lymphocyte-activation gene 3; DCs, dendritic cells; MDSCs, myeloid-derived suppressor cells; ILCs, innate lymphoid cells; NKs, natural killer cells; pDC, plasmacytoid dendritic cell; Treg, regulatory T cell; TIM3, T cell immunoglobulin and mucin-domain containing-3; M, macrophages; PtdSer, phosphatidylserine; HMGB1, high-mobility group box 1; CEACAM1, carcinoembryonic antigen-related cell adhesion molecule 1; TIGIT, T cell immunoreceptor with Ig and ITIM domains; APCs, antigen-presenting cells; NKG2A, natural killer group 2A; HLA-E, human leukocyte antigen E; ICIs, immune checkpoint inhibitors; ACTs, adoptive cell therapies; SIRPα, signal regulatory protein Alpha.

LAG-3 is an inhibitory immune checkpoint protein expressed by CD4+ and CD8+ T cells, NK cells, NKT cells, pDC cells, and B cells under antigen stimulation.140 LAG-3 can inhibit the cytokine secretion and anti-tumor effects of CD4+ T cells by competing with its highly homologous CD4 to bind MHC II.141 In addition, LAG-3 can also stimulate the immune suppression function of Treg cells and directly inhibit CD8+ T cells through signal transduction, ultimately exerting an immune suppression function.142,143 It is worth noting that LAG-3 expressed by pDC is a potential molecular target for restoring anti-tumor immune responses in melanoma.144 In a phase II/III clinical trial of unresectable or metastatic melanoma, the combination therapy of anti-LAG-3 antibody relatlimab and nivolumab (anti-PD-1 antibody) achieved positive results.145 Significantly, for patients with primary resistance to anti-PD-1/PD-L1 therapy, the combination of relatlimab and nivolumab plays therapeutic efficacy in the neoadjuvant treatment environment for advanced melanoma and non-pulmonary visceral metastasis (Figure 3).146

TIM-3, as an inhibitory immune checkpoint receptor, accelerates tumor proliferation and metastasis by inhibiting the activation of innate immune cells or adaptive immune cells through binding with its ligands (galectin 9, phosphatidylserine [PtdSer], carcinoembryonic antigen cell adhesion molecule 1 [CEACAM1], and high-mobility group box 1 [HMGB1]).139 TIM-3 is expressed on CD4+ and CD8+ T cells and on tumor-related DCs, macrophages, and NK cells.147 Although there is currently a lack of understanding of the role of TIM-3 in the previous non-T cells, more studies have shown that TIM-3 still plays a suppressive role in these cells. To date, clinical trials of three anti-TIM-3 antibodies have been completed: Sym023 (NCT03489343, NCT03311412), INCAGN02390 (NCT03652077), and sabatolimab (NCT04812548). They have achieved initial success in the safety and tolerance of monotherapy or combination therapy with other drugs for specific advanced solid tumors or hematological malignancies. In addition, in phase I clinical trial AMBER (NCT02817633), the combination therapy of the novel anti-TIM3 antibody cobolimab and the anti-PD-1 antibody dostarlimab achieved preliminary anti-tumor effects and acceptable tolerance in NSCLC, skin cancer, and peritoneal mesothelioma (Figure 3).148

TIGIT is a widely overexpressed inhibitory receptor on CD4+ and CD8+ T cells and is highly expressed in NK cells.149 TIGIT binds to its ligands CD155 (primary ligand, also known as PVR), CD112, CD113, Nectin4, and Fab2, which are expressed on tumor cells and APCs, causing overall immune suppression of cells.150,151 TIGIT mediates the exhausted phenotype characteristics of NK cells in the TME, specifically manifested as weakened killing ability, reduced cytokine production, and decreased proliferation function,152 and has been found to mediate T cell exhaustion in HCC,153 cervical cancer,154 and colorectal cancer.155 At present, clinical trials of monotherapy or combination therapy with anti-TIGIT antibodies and anti-PD-1 antibodies are being explored. It is worth noting that anti-TIGIT antibodies (vibostolimab, etigilimab, tiragolumab, ociperlimab) in the treatment of advanced solid tumors, and these anti-TIGIT antibodies combined with other immunotherapeutic agents (such as pembrolizumab, nivolumab, atezolizumab, and tislelizumab) have shown some clinical benefits.156,157,158,159 However, the efficacy and safety profiles of these anti-TIGIT antibodies necessitate further validation through large-scale clinical trials. Moreover, two distinct Phase III clinical trials were conducted for lung cancer, one targeting small cell lung cancer (SCLC) and the other NSCLC. These trials investigated the therapeutic effects of the anti-TIGIT antibody, tiragolumab, specifically in combination therapy regimens. Regrettably, the anticipated clinical outcomes were not achieved (NCT04256421 for SCLC, NCT04294810 for NSCLC) (Figure 3).

NKG2A, as a novel immune checkpoint, is an inhibitory receptor on the surface of NK cells. It forms a heterodimeric receptor with CD94 and binds to the non-classical MHC I molecule HLA-E to exert an inhibitory effect on the activity of NK cells.160,161,162 Importantly, widespread expression of HLA-E has been found on the surface of several types of human tumor cells.163 Therefore, monalizumab, as a humanized anti-NKG2A blocking monoclonal antibody, can promote the degranulation of NK cells (a way for NK cells to kill target cells) and stimulate the production of IFN-γ, increasing the anti-tumor effect of NK cells after blocking NKG2A.164 Interestingly, monalizumab can also amplify the therapeutic effect of other tumor immunotherapies, showing encouraging potential. For example, combining monalizumab and the anti-PD-L1 antibody durvalumab can increase the effector function of NK cells and CD8+ T cells.163 In addition, in a phase II clinical trial of head and neck squamous cell carcinoma, a combination therapy of monalizumab and cetuximab (an anti-epidermal growth factor receptor (EGFR) antibody) was carried out (NCT02643550). The interim report showed that compared to the overall response rate (ORR) of 13% in early studies of cetuximab monotherapy, the ORR showed a higher 27.5% after combination therapy in 40 evaluable patients (Figure 3).163,164

SIRPα is an inhibitory immune receptor carrying ITIM, expressed in myeloid cells (monocytes, granulocytes, DCs, especially macrophages).165 CD47 is overexpressed not only in normal cells but also in tumor cells. When SIRPα binds to CD47, it produces an immune suppression signal, preventing the immune system from mistakenly attacking itself and helping cancer cells evade immune cells.166,167 Therefore, blocking or disrupting the CD47/SIRPα pathway, which enhances the phagocytic activity against tumor cells, is currently a research hotspot in tumor immunotherapy and is being actively explored in a clinical context. For example, recently, there have been multiple treatments targeting the CD47/SIRPα pathway for monotherapy or combination therapy with other anti-cancer therapies, such as anti-CD47 antibodies, including magrolimab (NCT04599634) and recombinant fusion protein TTI-621 (NCT02663518) (Figure 3).

Chimeric antigen receptor innate immune cells

Chimeric Antigen Receptor (CAR)-T cells, as a type of engineered immune cell, are created by modifying T cells extracted from patients through ex vivo genetic engineering. This enables T cells to express CAR that specifically recognize and attack tumor cells with specific antigens. Currently, CAR-T cell therapy has emerged as a prominent clinical strategy for cancer immunotherapy, achieving significant results in treating hematological malignancies (such as MM, B cell lymphoma, B cell lymphocytic leukemia).168,169 However, elevated off-target risks, solid tumor physical barriers, and immunosuppressive TME lead to the poorer performance of CAR-T cell therapy in treating solid tumors. At the same time, distinct adverse effects associated with CAR-T cell therapy, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenia, and graft versus host disease (GvHD), pose significant clinical challenges.170,171 Consequently, these challenges have motivated exploring alternative strategies in immune cell engineering, such as CAR-NK and CAR-macrophage (CAR-M) therapies (Figure 4).Figure 4 The working principle of novel immunotherapies based on innate immune cells

(A) The efficacy of CAR-T cells against solid tumors is limited due to the immunosuppressive effects of the TME, solid tumor barrier, and off-target risks.

(B) CAR-NK cells exert tumor-killing effects through both CAR-dependent and independent mechanisms.

(C) CAR-macrophages exhibit high infiltration capability and exert anti-tumor effects through tumor antigen presentation and phagocytosis.

(D) Working model of DC cancer vaccines. Tumor antigen-expressing mRNA is pulsed into DCs. The antigen-presenting DCs can activate anti-tumor immunity after being injected into patients.

(E) CAR-NK clinical trials target different tumor antigens. NKG2D and PSMA are antigens of solid tumors, while BCMA, CD19, and CD123 are antigens of hematological malignancies. Abbreviations: CAR-T, chimeric antigen receptor T cell; TME, tumor microenvironment; DCs, dendritic cells; CAR-NK, chimeric antigen receptor natural killer cell; CAR-macrophages, chimeric antigen receptor macrophages; mRNA, messenger RNA; NKG2D, natural killer group 2D; PSMA, prostate-specific membrane antigen; BCMA, B cell maturation antigen; CD19, cluster of differentiation 19; CD123, cluster of differentiation 123.

Compared to CAR-T cells, CAR-innate immune cells have shown preliminary success against hematological malignancies in clinical research and have also shown advantages in treating solid tumors. For example, although CAR-T cells target specific cancer antigens through chimeric antigen receptors, they still express their native TCRs. When CAR-T cells are derived from allogeneic sources, they may recognize the MHC of the recipient as foreign. This recognition triggers an immune response against the recipient tissues, leading to GvHD. In contrast, CAR-engineered innate immune cells such as CAR-M, CAR-NK, and CAR-engineered innate T cells do not rely on MHC molecules to recognize and attack target cells, bypassing the primary trigger for GvHD. This characteristic enables the production of off-the-shelf CAR-engineered innate immune cell therapies that can be prepared and made available to multiple patients, enhancing safety and accessibility.172 Additionally, CAR-NK cells can utilize target-specific killing and innate anti-tumor abilities, killing target-expressing cancer cells through CAR-mediated killing mechanisms and killing target-lacking cancer cells through CAR-independent or innate NK cell toxicity-mediated mechanisms.173 CAR-M cells rely on phagocytosis, tumor antigen presentation, and tumor infiltration abilities. Therefore, both can effectively kill solid tumors. Currently, clinical trials of CAR-NK are mainly focused on targeting these markers of hematological malignancies: CD19 (NCT05410041, NCT05645601, NCT05667155, NCT05673447, NCT05739227), CD123 (NCT06006403, NCT05574608, NCT06201247), and BCMA (NCT05652530, NCT06045091). At the same time, some clinical trials are actively exploring the application of CAR-NK cells in the treatment of metastatic or recurrent/refractory solid tumors, mainly targeting NKG2D (NCT05528341, NCT05248048, NCT05213195, NCT05776355) and PSMA (NCT03692663). Finally, it is worth noting that two ongoing clinical trials recently registered on clinicaltrials.gov aim to explore the safety and effectiveness of CAR-M cell therapy for HER2-overexpressing solid tumors (NCT06224738, NCT04660929). The conduct of these clinical trials provides valuable experience for us to deeply understand the feasibility and potential of CAR non-T cells in the treatment of cancer (Figure 4).

STING/CD40 agonists

Currently, agonists targeting the immune system have demonstrated significant promise as cancer immunotherapies. Notably, STING and CD40 agonists are crucial in bridging innate and adaptive immune responses, showcasing substantial potential in tumor treatment. Tumor-specific adaptive immune responses, exemplified by CD8+ T cells, rely on IFN-I signaling within APCs. The cGAS/STING pathway, a critical regulator of IFN-I signaling, activates various anti-tumor functions in adaptive immune cells by triggering innate immune signaling pathways.174 The cGAS/STING pathway responds to pathogenic infections, DNA damage, abnormal cellular replication, and senescence. These processes generate abnormal double-stranded DNA, which is recognized by cGAS, subsequently catalyzing the production of cyclic GMP-AMP (cGAMP). cGAMP binds to the endoplasmic reticulum membrane receptor STING, inducing STING oligomerization and translocation to the Golgi apparatus, thereby recruiting and activating downstream TBK1/IRF3/IFN-I or TBK1/NF-κB signaling cascades.174,175

DCs are considered the primary innate immune cells in the TME that produce IFN-I. STING agonists enhance DC-mediated tumor antigen presentation and subsequent anti-tumor CD8+ T cell responses.174 Additionally, novel STING agonists, such as di-ABZI, MSA-2, and manganese, can enhance the expression of costimulatory molecules and MHC on DCs and improve the ability of DCs to prime and properly activate antigen-specific CD8+ T cells, demonstrating significant anti-tumor potential in tumor models and are currently in clinical trials.175,176,177,178,179 Notably, manganese, as an STING agonist, can also promote macrophage maturation and tumor-specific antigen presentation, enhancing CD8+ T cell and NK cell activation, thus boosting cytotoxicity mediated by CD8+ T cells and NK cells.177 Overall, STING agonists mobilize innate immune sensors within the TME for immune surveillance and activate tumor-targeting T cell responses.2

CD40, a member of the TNF receptor superfamily, is expressed by various types of immune cells, including B lymphocytes, DCs, and monocytes.178,179 CD40 activation modulates the TME independently of innate immune sensors such as Toll-like receptors (TLRs) and STING. The ligand of CD40, CD40L (CD154), primarily located on activated T cells, triggers critical immune responses through CD40−CD40L interactions, including licensing DCs to activate CD8+ T cells.179 It was also reported that CD8+ T cells can upregulate IL-12 expression in DCs via CD40L-CD40 interactions, promoting their proliferation and differentiation and forming a positive feedback loop for anti-tumor activity.180 Moreover, in epithelial cancers and melanoma, the binding of CD40L to CD40 can mediate immunogenic cell death, activating DCs within the TME.181,182 Similarly, CD40L stimulation leads to increased secretion of IL-12 by DCs and macrophages, which perpetuates Th1 responses and activates NK cell anti-tumor activity.183 In macrophages, CD40 receptor ligation increases IFN-γ, TNF-α, T cell-dependent nitric oxide production, and antibody-dependent cellular cytotoxicity (ADCC), contributing to tumor suppression.179 Additionally, CD40-activated macrophages can induce apoptosis in tumor cells in vitro, such as in mouse lymphoma cells (L5178Y).184 Notably, selicrelumab, one of the most extensively studied CD40 agonists in clinical trials, modulates the TME by inducing DC maturation and macrophage polarization.185 Although CD40 agonists are still developing, their critical role in activating antitumor immune responses within the TME makes them promising targets for cancer immunotherapies.

Drug delivery based on innate immune cells

Using innate immune cells to deliver anti-tumor drugs is an emerging drug delivery method. Innate immune cells naturally tend to migrate to sites of tissue damage and inflammation, which is the feature of TME. As a result, immune cells are continuously recruited to tumor sites. Additionally, self-recognition signals on innate immune cells ensure that the drugs they carry are not rapidly cleared, thereby improving drug efficacy, extending half-life, reducing immunogenicity, and minimizing off-target effects and related adverse reactions.186 These characteristics make innate immune cells potentially excellent drug delivery carriers. The application of macrophages and neutrophils in drug delivery has been extensively explored, so this section focuses on these two cell types.186,187

As anti-tumor drug carriers, macrophages have natural advantages. They circulate in the bloodstream like red blood cells and neutrophils and target tumor tissues through their α4 and β1 integrins, which bind to vascular cell adhesion molecule 1 (VCAM-1) of cancer cells.187 Drugs can be directly loaded in macrophages or incorporated into nanoparticles before loading into macrophages.188 As directly loaded drugs may kill macrophages, the latter approach is more often deployed for macrophage-based drug delivery systems. For example, Choi et al. developed peritoneal macrophages loaded with DOX-liposomes (doxorubicin-loaded liposomes), which showed higher tumor metastasis inhibition than DOX-liposomes alone.189 Additionally, macrophages can cross the blood-brain barrier (BBB) to deliver drugs to brain tumors. However, challenges such as large-scale production difficulties and quality control issues of human macrophages hinder the clinical translation of engineered macrophages.188 The strategy of using neutrophils as anti-tumor drug carriers is similar to that of macrophages, including using neutrophils directly as drug carriers and indirect drug carriers (encapsulating drugs in nanoparticles such as liposomes),190 and using neutrophil-derived exosomes for drug delivery.191 Neutrophils can also cross the BBB, making them potential drug carriers for treating brain tumors.192 However, due to their short lifespan and the potential damage caused to healthy tissues through degranulation, the application of neutrophils as drug delivery carriers has certain limitations.186

Surface backpack anchoring

In recent years, various strategies have been proposed to regulate the phenotypes of adoptively transferred macrophages to treat tumors, autoimmune disorders, and inflammatory diseases. Recent studies have shown that engineered particles containing IFN-γ, defined as “backpacks”, can evade phagocytosis for days and adhere firmly to macrophages, inducing their polarization. This allows the macrophages to maintain their cytotoxicity deep within the immunosuppressive TME, enhancing anti-tumor responses.193 Similarly, another study developed IFN-γ-modified backpacks to control monocyte differentiation, effectively slowing solid tumor progression due to the intense tumor tissue infiltration of monocytes.194 Using a similar approach, immunogenic bacteria were used as backpacks to attach to macrophages for the reprogramming of TAMs to provide a more sustained and robust immune response, leading to the inhibition of tumor progression with reduced side effects.195

Ex vivo polarization of macrophage

Notably, due to the high heterogeneity and plasticity of TAMs in the TME, altering TAM behavior in situ is difficult to control and predict. Alternatively, macrophages are polarized ex vivo and then adoptively transferred for tumor control. The first attempt dates back to 1990, when blood monocytes were isolated, cultured with autologous serum, and induced with INF-γ to differentiate into autologous M1 macrophages for tumor therapy.196 These macrophages effectively targeted and killed tumor cells without harming normal cells in vivo. Subsequent studies on activated macrophages using similar principles demonstrated high efficacy against lymphoma, ovarian cancer, and other types of cancer.197 Importantly, in vitro polarized macrophage therapy appears safe, with minimal severe adverse events reported.198

Cancer vaccines

Compared to traditional prophylactic vaccines, therapeutic cancer vaccines are designed to target established cancers. They induce an immune response to specific antigens to eliminate tumors and maintain a lasting immune effect to prevent cancer recurrence. Currently, cancer vaccines that are based on the APCs of patients have demonstrated significant potential in the field of tumor immunotherapy. For example, the therapeutic cancer vaccine sipuleucel-T (Provenge) became the first FDA-approved autologous ex vivo APC-based cancer vaccine in 2010. It was successful in a phase III clinical trial (NCT00065442) for the treatment of metastatic castration-resistant prostate cancer, ushering in a new era for cancer immunotherapy. Notably, in a recent phase II clinical trial for metastatic castration-resistant prostate cancer, researchers further explored whether the combination of sipuleucel-T and novel hormone drugs (NHAs) could enhance the activation of APCs (NCT05751941).

DCs, as the most effective APCs in the immune system, are used to prepare DC cancer vaccines by loading cancer antigens or transfecting antigen genes. For instance, mRNA ex vivo pulsed DC vaccines represent an innovative approach in tumor immunotherapy. The working principle involves using pulses to introduce mRNA, which encodes cancer antigens, into DCs ex vivo. This allows the DCs to encode and present the cancer antigens. Subsequently, the DCs mature under ex vivo conditions and are reintroduced into the patient’s body, triggering an anti-tumor immune response.199 This method effectively harnesses the immune system of patients to fight against cancer. This type of vaccine has been successfully validated in clinical trials for various types of cancer, especially glioblastoma (NCT00846456, NCT02808364, NCT02366728) and malignant melanoma (NCT01278940, NCT00243529). In current research trends, it is worth noting that clinical trials of DC cancer vaccines are exploring combination treatment strategies with chemotherapy (NCT02649829, NCT02649582), traditional prophylactic vaccines (NCT03615404, NCT03334305), antibody-targeted therapy (NCT00626483, NCT02366728, NCT01876212, NCT00626483), and ICIs (NCT05767684, NCT02529072, NCT0130249) (Figure 4).

Conclusion and perspectives

Innate immune cells, tumor cells, adaptive immune cells, and other TME components interact to form a complex ecosystem. This review provides a comprehensive and systematic analysis of the heterogeneity and plasticity of various subgroups of innate immune cells within the TME. We also integrate the current innovative cancer immunotherapies associated with innate immune cells, exploring their clinical features and potential. This emphasizes the importance of expanding our current understanding of the role of innate immune cells in anti-tumor therapy.

Innate immune cells within the TME exhibit significant heterogeneity. In terms of their pro-tumor and anti-tumor phenotypes, except for NK cells, which predominantly have anti-tumor functions and MDSCs, which predominantly have pro-tumor functions, other cell types display both pro-tumor and anti-tumor phenotypes. At the molecular level, nearly all cell types demonstrate heterogeneity. How is heterogeneity generated? From the perspective of immune cells themselves, the transcriptome undergoes continuous changes during their developmental processes. The inflammatory environment of the TME not only recruits mature innate immune cells but attracts immature innate immune cells through various chemokines. These immature immune cells generally activate immunosuppressive signaling pathways, manifesting as pro-tumor phenotypes. Furthermore, the phenotype of immune cells is highly dynamic and susceptible to environmental influences. Interactions between cells (including interactions between immune cells, immune cells and tumor cells, and between immune cells and tissue cells), regulation by cytokines and chemokines, and the chemical environment (such as oxygen concentration, pH, and metabolic products) all contribute to this process. Different environmental stimuli activate different signaling pathways, activating distinct transcription factors, ultimately leading to diverse gene expression patterns. The heterogeneity of immune cells is found not only in their pro-tumor and anti-tumor phenotypes but also at the molecular level, with the development of single-cell resolution techniques. Phenotypic differences fundamentally arise from variations in gene expression, which are reflected in the RNA and protein expression levels. Current techniques for studying heterogeneity include RNA expression analysis (such as scRNA-seq and spatial transcriptomics) and membrane/cytoplasmic protein level analysis (such as flow cytometry, CyTOF, immunohistochemistry, and mass spectrometry). It is important to note that molecular data do not always perfectly correlate with phenotypes. For instance, CD163+ and CD206+ macrophages, typically considered pro-tumor at the molecular level, can stimulate T cell activity in gastrointestinal tumors.200 Another example is MDSCs, which were initially defined based on their functional phenotypes and later characterized by molecular markers. The PMN-MDSC marker CD11b+ Ly6G+ Ly6Clow does not distinguish them from neutrophils.96 High-throughput experimental data have shown that MDSC populations exhibit extreme heterogeneity, making molecular definition challenging and leading to skepticism about the existence of MDSC subtypes.201

Numerous innate immune cells in the TME form an interconnected system. Cellular interactions are a crucial factor contributing to the heterogeneity of innate immune cells and a key focus and challenge in TME research. Studying cellular interactions involves several key aspects: (1) identifying specific cell types, (2) observing spatial relationships, and (3) determining interaction patterns and pathways. Due to heterogeneity, research on interactions often requires single-cell resolution molecular information.202 The most relevant samples for studying the TME are surgical specimens obtained from patient tumors. However, dynamic studies cannot be conducted on fixed or frozen tumor tissues.202 Organoids can partially address the limited availability of patient tumor samples, making genetic manipulation and high-throughput analysis feasible.203 In vitro cancer cell lines are commonly used models for studying cellular interactions in the laboratory. Co-culturing tumor cell lines with innate immune cells allow exploration of their interactions. However, the limited types of co-cultured cells and the inability to replicate the conditions within the TME do not fully reflect the in vivo situation. To mimic the in vivo environment, tumors can be subcutaneously transplanted into immunocompromised mice. However, the TME established by transplanted tumors is not as well-developed as that of primary tumors. Additionally, the compromised immune system of these mouse models does not recapitulate the clinical conditions. Traditional microscopy techniques, such as IHC, focus on analyzing the spatial location of cells but are poor at molecular profiling. Techniques based on cell sorting can achieve high-throughput molecular analysis but lose spatial information due to the need for dissociation. New technologies, such as imaging mass spectrometry, cyclic IHC, and imaging-based transcriptomics, can integrate spatial and molecular expression patterns, potentially providing new insights into the interactions of innate immune cells within the TME.202

In humans, adoptive cell therapy typically involves primary cells isolated from peripheral blood. However, the limited availability of primary cells and the difficulty in ex vivo expansion pose significant challenges to the large-scale clinical application of primary cell-based therapies. Additionally, the variability among donors, the difficulty in isolating tissue-resident cells, and the insufficient number of cells for screening all impact cellular therapy development and drug invention.204 One common approach to overcome these limitations is using tumor or immortalized cell lines such as THP-1. However, these continuously dividing cells have limited capacity to simulate in vivo conditions, typically used for drug screening.204 Another approach is using human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), which possess self-renewal capabilities and pluripotency, providing an unlimited supply of immune cells.205 Using hESC or iPSC-derived engineered cell products allows for individual clone isolation and off-target genome alteration detection through whole-genome sequencing. This method also permits the effective addition of multiple genetic modifications to enhance the cytotoxicity of immune cells.206 Especially, iPSC technology enables the generation of hPSCs without human embryos, addressing tissue incompatibility and ethical issues associated with human ES cells.207

iPSC-derived innate immune cells have been studied in therapies involving macrophages, NK cells, and DCs. Zhu et al. engineered a high-affinity, non-cleavable variant of CD16a (hnCD16) into iPSCs to create hnCD16-iNK cells with enhanced ADCC. When combined with therapeutic antibodies, these hnCD16-iNK cells showed significantly improved efficacy against B cell lymphoma and ovarian cancer in xenograft models.208 The proliferation capacity of myeloid cells, such as macrophages, is quite limited. Haruta et al. transduced genes involved in cell growth or senescence inhibition (e.g., c-MYC, BMI1, MDM2, or EZH2) to generate human iPSC-derived proliferative myeloid cells. These cells can increase for several months and function as iMacs cell209 or differentiate into iDCs within 2–3 days210 Engineered iNK and iMacs can not only act directly but also serve as targets for CAR editing to produce CAR-iNKs211 or CAR-iMacs.212 iPSC-derived iDCs can be used as precursor cells for DC vaccines.213 Overall, iPSC-derived innate immune cells offer the opportunity to produce large amounts of well-controlled and ready-to-use products, heralding a new era in tumor immunotherapy.

Acknowledgments

This work was supported by 10.13039/501100004835 Zhejiang University - University of Edinburgh Institute (ZJE) and the Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, 10.13039/501100004835 Zhejiang University . We also acknowledge the help of members in J.L.’s lab.

This work was supported by grants to J.Liu from the NSF of Zhejiang Province (Distinguished Young Scholars: LR22H160002 ), the 10.13039/501100001809 Natural Science Foundation (NSF) of China (general grant: 82172899 ), Dr. Li Dak Sum and Yip Yio Chin Development Fund for Regenerative Medicine, 10.13039/501100004835 Zhejiang University , the Open Fund of Zhejiang Provincial Key Laboratory of Pulmonology (KF202302 ). This work was partly supported by the Dynamic Research Enterprise for Multidisciplinary Engineering Sciences (DREMES) at 10.13039/501100004835 Zhejiang University and the 10.13039/100005302 University of Illinois at Urbana-Champaign , funded by 10.13039/501100004835 Zhejiang University . The work was led by Principal Supervisor Jian Liu.

Author contributions

J.L. and S.M. designed, supervised, and supported the whole project. C.Li. wrote the manuscript. X.Y., X.H., C.Lian., Z.W., S.S., F.S., and H.W. revised the manuscript. X.Y. contributed to some figures and a few parts of the manuscript. All authors contributed to the review and approved the submitted version.

Declaration of interests

The authors declare no competing interests.
==== Refs
References

1 Xiao Y. Yu D. Tumor microenvironment as a therapeutic target in cancer Pharmacol. Ther. 221 2021 107753 10.1016/j.pharmthera.2020.107753
2 Yi M. Li T. Niu M. Mei Q. Zhao B. Chu Q. Dai Z. Wu K. Exploiting innate immunity for cancer immunotherapy Mol. Cancer 22 2023 187 10.1186/s12943-023-01885-w 38008741
3 Szeto G.L. Finley S.D. Integrative Approaches to Cancer Immunotherapy Trends Cancer 5 2019 400 410 10.1016/j.trecan.2019.05.010 31311655
4 Hollingsworth R.E. Jansen K. Turning the corner on therapeutic cancer vaccines npj Vaccines 4 2019 7 10 10.1038/s41541-019-0103-y 30774998
5 O’Donnell J.S. Teng M.W.L. Smyth M.J. Cancer immunoediting and resistance to T cell-based immunotherapy Nat. Rev. Clin. Oncol. 16 2019 151 167 10.1038/s41571-018-0142-8 30523282
6 Stein M. Keshav S. Harris N. Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation J. Exp. Med. 176 1992 287 292 10.1084/jem.176.1.287 1613462
7 Mills C.D. Kincaid K. Alt J.M. Heilman M.J. Hill A.M. M-1/M-2 Macrophages and the Th1/Th2 Paradigm J. Immunol. 164 2000 6166 6173 10.4049/jimmunol.164.12.6166 10843666
8 Sica A. Mantovani A. Macrophage plasticity and polarization: in vivo veritas J. Clin. Invest. 122 2012 787 795 10.1172/JCI59643 22378047
9 Funes S.C. Rios M. Escobar-Vera J. Kalergis A.M. Implications of macrophage polarization in autoimmunity Immunology 154 2018 186 195 10.1111/imm.12910 29455468
10 Muntjewerff E.M. Meesters L.D. van den Bogaart G. Antigen Cross-Presentation by Macrophages Front. Immunol. 11 2020 1276 10.3389/fimmu.2020.01276 32733446
11 Martin M.D. Badovinac V.P. Defining Memory CD8 T Cell Front. Immunol. 9 2018 2692 10.3389/fimmu.2018.02692 30515169
12 Embgenbroich M. Burgdorf S. Current Concepts of Antigen Cross-Presentation Front. Immunol. 9 2018 1643 10.3389/fimmu.2018.01643 30061897
13 Arango Duque G. Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases Front. Immunol. 5 2014 491 10.3389/fimmu.2014.00491 25339958
14 Mantovani A. Marchesi F. Malesci A. Laghi L. Allavena P. Tumour-associated macrophages as treatment targets in oncology Nat. Rev. Clin. Oncol. 14 2017 399 416 10.1038/nrclinonc.2016.217 28117416
15 Xiang X. Wang J. Lu D. Xu X. Targeting tumor-associated macrophages to synergize tumor immunotherapy Signal Transduct. Targeted Ther. 6 2021 75 10.1038/s41392-021-00484-9
16 Wu K. Lin K. Li X. Yuan X. Xu P. Ni P. Xu D. Redefining Tumor-Associated Macrophage Subpopulations and Functions in the Tumor Microenvironment Front. Immunol. 11 2020 1731 10.3389/fimmu.2020.01731 32849616
17 Biswas S.K. Allavena P. Mantovani A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions Semin. Immunopathol. 35 2013 585 600 10.1007/s00281-013-0367-7 23657835
18 Zhu X. Liang R. Lan T. Ding D. Huang S. Shao J. Zheng Z. Chen T. Huang Y. Liu J. Tumor-associated macrophage-specific CD155 contributes to M2-phenotype transition, immunosuppression, and tumor progression in colorectal cancer J. Immunother. Cancer 10 2022 e004219 10.1136/jitc-2021-004219
19 Li H. Yang P. Wang J. Zhang J. Ma Q. Jiang Y. Wu Y. Han T. Xiang D. HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk J. Hematol. Oncol. 15 2022 2 10.1186/s13045-021-01223-x 34991659
20 Xu R. Lee Y.-J. Kim C.-H. Min G.-H. Kim Y.-B. Park J.-W. Kim D.-H. Kim J.-H. Yim H. Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1 J. Exp. Clin. Cancer Res. 42 2023 302 10.1186/s13046-023-02872-1 37968723
21 Weng Y.-S. Tseng H.-Y. Chen Y.-A. Shen P.-C. Al Haq A.T. Chen L.-M. Tung Y.-C. Hsu H.-L. MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer Mol. Cancer 18 2019 42 10.1186/s12943-019-0988-0 30885232
22 Du S. Qian J. Tan S. Li W. Liu P. Zhao J. Zeng Y. Xu L. Wang Z. Cai J. Tumor cell-derived exosomes deliver TIE2 protein to macrophages to promote angiogenesis in cervical cancer Cancer Lett. 529 2022 168 179 10.1016/j.canlet.2022.01.005 35007697
23 Eisel D. Das K. Dickes E. König R. Osen W. Eichmüller S.B. Cognate Interaction With CD4+ T Cells Instructs Tumor-Associated Macrophages to Acquire M1-Like Phenotype Front. Immunol. 10 2019 219
24 Han S. Bao X. Zou Y. Wang L. Li Y. Yang L. Liao A. Zhang X. Jiang X. Liang D. d -lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma Sci. Adv. 9 2023 eadg2697 10.1126/sciadv.adg2697
25 Johnson D.E. O’Keefe R.A. Grandis J.R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer Nat. Rev. Clin. Oncol. 15 2018 234 248 10.1038/nrclinonc.2018.8 29405201
26 Yang T. Han Y. Chen J. Liang X. Sun L. MiR-506 Promotes Antitumor Immune Response in Pancreatic Cancer by Reprogramming Tumor-Associated Macrophages toward an M1 Phenotype Biomedicines 11 2023 2874 10.3390/biomedicines11112874 38001876
27 Miao L. Qi J. Zhao Q. Wu Q.-N. Wei D.-L. Wei X.-L. Liu J. Chen J. Zeng Z.-L. Ju H.-Q. Targeting the STING pathway in tumor-associated macrophages regulates innate immune sensing of gastric cancer cells Theranostics 10 2020 498 515 10.7150/thno.37745 31903134
28 Gholamin S. Mitra S.S. Feroze A.H. Liu J. Kahn S.A. Zhang M. Esparza R. Richard C. Ramaswamy V. Remke M. Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors Sci. Transl. Med. 9 2017 eaaf2968 10.1126/scitranslmed.aaf2968
29 Rodriguez-Garcia A. Lynn R.C. Poussin M. Eiva M.A. Shaw L.C. O’Connor R.S. Minutolo N.G. Casado-Medrano V. Lopez G. Matsuyama T. Powell D.J. Jr. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy Nat. Commun. 12 2021 877 10.1038/s41467-021-20893-2 33563975
30 Sánchez-Paulete A.R. Mateus-Tique J. Mollaoglu G. Nielsen S.R. Marks A. Lakshmi A. Khan J.A. Wilk C.M. Pia L. Baccarini A. Targeting Macrophages with CAR T Cells Delays Solid Tumor Progression and Enhances Antitumor Immunity Cancer Immunol. Res. 10 2022 1354 1369 10.1158/2326-6066.CIR-21-1075 36095236
31 Ruf B. Bruhns M. Babaei S. Kedei N. Ma L. Revsine M. Benmebarek M.-R. Ma C. Heinrich B. Subramanyam V. Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin Cell 186 2023 3686 3705.e32 10.1016/j.cell.2023.07.026 37595566
32 See P. Dutertre C.-A. Chen J. Günther P. McGovern N. Irac S.E. Gunawan M. Beyer M. Händler K. Duan K. Mapping the human DC lineage through the integration of high-dimensional techniques Science 356 2017 eaag3009 10.1126/science.aag3009
33 Plesca I. Müller L. Böttcher J.P. Medyouf H. Wehner R. Schmitz M. Tumor-associated human dendritic cell subsets: Phenotype, functional orientation, and clinical relevance Eur. J. Immunol. 52 2022 1750 1758 10.1002/eji.202149487 35106759
34 Mitchell D. Chintala S. Dey M. Plasmacytoid dendritic cell in immunity and cancer J. Neuroimmunol. 322 2018 63 73 10.1016/j.jneuroim.2018.06.012 30049538
35 Veglia F. Gabrilovich D.I. Dendritic cells in cancer: the role revisited Curr. Opin. Immunol. 45 2017 43 51 10.1016/j.coi.2017.01.002 28192720
36 Giampazolias E. Schulz O. Lim K.H.J. Rogers N.C. Chakravarty P. Srinivasan N. Gordon O. Cardoso A. Buck M.D. Poirier E.Z. Secreted gelsolin inhibits DNGR-1-dependent cross-presentation and cancer immunity Cell 184 2021 4016 4031.e22 10.1016/j.cell.2021.05.021 34081922
37 Bayerl F. Meiser P. Donakonda S. Hirschberger A. Lacher S.B. Pedde A.-M. Hermann C.D. Elewaut A. Knolle M. Ramsauer L. Tumor-derived prostaglandin E2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses Immunity 56 2023 1341 1358.e11 10.1016/j.immuni.2023.05.011 37315536
38 Bauer C.A. Kim E.Y. Marangoni F. Carrizosa E. Claudio N.M. Mempel T.R. Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction J. Clin. Invest. 124 2014 2425 2440 10.1172/JCI66375 24812664
39 Minn A.J. Wherry E.J. Combination Cancer Therapies with Immune Checkpoint Blockade: Convergence on Interferon Signaling Cell 165 2016 272 275 10.1016/j.cell.2016.03.031 27058661
40 Moreno Ayala M.A. Campbell T.F. Zhang C. Dahan N. Bockman A. Prakash V. Feng L. Sher T. DuPage M. CXCR3 expression in regulatory T cells drives interactions with type I dendritic cells in tumors to restrict CD8+ T cell antitumor immunity Immunity 56 2023 1613 1630.e5 10.1016/j.immuni.2023.06.003 37392735
41 Suthen S. Lim C.J. Nguyen P.H.D. Dutertre C.-A. Lai H.L.H. Wasser M. Chua C. Lim T.K.H. Leow W.Q. Loh T.J. Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC Hepatology 76 2022 1329 1344 10.1002/hep.32419 35184329
42 Raychaudhuri D. Bhattacharya R. Sinha B.P. Liu C.S.C. Ghosh A.R. Rahaman O. Bandopadhyay P. Sarif J. D’Rozario R. Paul S. Lactate Induces Pro-tumor Reprogramming in Intratumoral Plasmacytoid Dendritic Cells Front. Immunol. 10 2019 1878 10.3389/fimmu.2019.01878 31440253
43 Chevolet I. Speeckaert R. Schreuer M. Neyns B. Krysko O. Bachert C. Hennart B. Allorge D. van Geel N. Van Gele M. Brochez L. Characterization of the in vivo immune network of IDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells in melanoma OncoImmunology 4 2015 e982382 10.4161/2162402X.2014.982382
44 Demoulin S. Herfs M. Somja J. Roncarati P. Delvenne P. Hubert P. HMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells Int. J. Cancer 137 2015 345 358 10.1002/ijc.29389 25492101
45 Terra M. Oberkampf M. Fayolle C. Rosenbaum P. Guillerey C. Dadaglio G. Leclerc C. Tumor-Derived TGFβ Alters the Ability of Plasmacytoid Dendritic Cells to Respond to Innate Immune Signaling Cancer Res. 78 2018 3014 3026 10.1158/0008-5472.CAN-17-2719 29523540
46 Brown S. Hutchinson C.V. Aspinall-O’Dea M. Whetton A.D. Johnson S.M. Rees-Unwin K. Burthem J. Monocyte-derived dendritic cells from chronic myeloid leukaemia have abnormal maturation and cytoskeletal function that is associated with defective localisation and signalling by normal ABL1 protein Eur. J. Haematol. 93 2014 96 102 10.1111/ejh.12306 24617663
47 Tesone A.J. Rutkowski M.R. Brencicova E. Svoronos N. Perales-Puchalt A. Stephen T.L. Allegrezza M.J. Payne K.K. Nguyen J.M. Wickramasinghe J. Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells Cell Rep. 14 2016 1774 1786 10.1016/j.celrep.2016.01.056 26876172
48 Toniolo P.A. Liu S. Yeh J.E. Ye D.Q. Barbuto J.A.M. Frank D.A. Deregulation of SOCS5 suppresses dendritic cell function in chronic lymphocytic leukemia Oncotarget 7 2016 46301 46314 10.18632/oncotarget.10093 27317770
49 Böttcher J.P. Reis e Sousa C. The Role of Type 1 Conventional Dendritic Cells in Cancer Immunity Trends Cancer 4 2018 784 792 10.1016/j.trecan.2018.09.001 30352680
50 Schenkel J.M. Herbst R.H. Canner D. Li A. Hillman M. Shanahan S.-L. Gibbons G. Smith O.C. Kim J.Y. Westcott P. Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes Immunity 54 2021 2338 2353.e6 10.1016/j.immuni.2021.08.026 34534439
51 Ferris S.T. Durai V. Wu R. Theisen D.J. Ward J.P. Bern M.D. Davidson J.T. Bagadia P. Liu T. Briseño C.G. cDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity Nature 584 2020 624 629 10.1038/s41586-020-2611-3 32788723
52 Wu R. Ohara R.A. Jo S. Liu T.-T. Ferris S.T. Ou F. Kim S. Theisen D.J. Anderson D.A. Wong B.W. Mechanisms of CD40-dependent cDC1 licensing beyond costimulation Nat. Immunol. 23 2022 1536 1550 10.1038/s41590-022-01324-w 36271147
53 Guo C. You Z. Shi H. Sun Y. Du X. Palacios G. Guy C. Yuan S. Chapman N.M. Lim S.A. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity Nature 620 2023 200 208 10.1038/s41586-023-06299-8 37407815
54 James C.A. Baer J.M. Zou C. Panni U.Y. Knolhoff B.L. Hogg G.D. Kingston N.L. Kang L.-I. Lander V.E. Luo J. Systemic Alterations in Type-2 Conventional Dendritic Cells Lead to Impaired Tumor Immunity in Pancreatic Cancer Cancer Immunol. Res. 11 2023 1055 1067 10.1158/2326-6066.CIR-21-0946 37229629
55 Santegoets S.J. Duurland C.L. Jordanova E.J. van Ham V.J. Ehsan I. Loof N.M. Narang V. Dutertre C.A. Ginhoux F. van Egmond S.L. CD163+ cytokine-producing cDC2 stimulate intratumoral type 1 T cell responses in HPV16-induced oropharyngeal cancer J. Immunother. Cancer 8 2020 e001053 10.1136/jitc-2020-001053
56 Koucký V. Bouček J. Fialová A. Immunology of Plasmacytoid Dendritic Cells in Solid Tumors: A Brief Review Cancers 11 2019 470 10.3390/cancers11040470 30987228
57 Poropatich K. Dominguez D. Chan W.-C. Andrade J. Zha Y. Wray B. Miska J. Qin L. Cole L. Coates S. OX40+ plasmacytoid dendritic cells in the tumor microenvironment promote antitumor immunity J. Clin. Invest. 130 2020 3528 3542 10.1172/JCI131992 32182225
58 Wu J. Li S. Yang Y. Zhu S. Zhang M. Qiao Y. Liu Y.-J. Chen J. TLR-activated plasmacytoid dendritic cells inhibit breast cancer cell growth in vitro and in vivo Oncotarget 8 2017 11708 11718 10.18632/oncotarget.14315 28052019
59 Wculek S.K. Cueto F.J. Mujal A.M. Melero I. Krummel M.F. Sancho D. Dendritic cells in cancer immunology and immunotherapy Nat. Rev. Immunol. 20 2020 7 24 10.1038/s41577-019-0210-z 31467405
60 Fridlender Z.G. Sun J. Kim S. Kapoor V. Cheng G. Ling L. Worthen G.S. Albelda S.M. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN Cancer Cell 16 2009 183 194 10.1016/j.ccr.2009.06.017 19732719
61 Salcher S. Sturm G. Horvath L. Untergasser G. Kuempers C. Fotakis G. Panizzolo E. Martowicz A. Trebo M. Pall G. High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer Cancer Cell 40 2022 1503 1520.e8 10.1016/j.ccell.2022.10.008 36368318
62 Xue R. Zhang Q. Cao Q. Kong R. Xiang X. Liu H. Feng M. Wang F. Cheng J. Li Z. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity Nature 612 2022 141 147 10.1038/s41586-022-05400-x 36352227
63 Granot Z. Henke E. Comen E.A. King T.A. Norton L. Benezra R. Tumor entrained neutrophils inhibit seeding in the premetastatic lung Cancer Cell 20 2011 300 314 10.1016/j.ccr.2011.08.012 21907922
64 Cui C. Chakraborty K. Tang X.A. Zhou G. Schoenfelt K.Q. Becker K.M. Hoffman A. Chang Y.-F. Blank A. Reardon C.A. Neutrophil elastase selectively kills cancer cells and attenuates tumorigenesis Cell 184 2021 3163 3177.e21 10.1016/j.cell.2021.04.016 33964209
65 Meng Y. Ye F. Nie P. Zhao Q. An L. Wang W. Qu S. Shen Z. Cao Z. Zhang X. Immunosuppressive CD10+ALPL+ neutrophils promote resistance to anti-PD-1 therapy in HCC by mediating irreversible exhaustion of T cells J. Hepatol. 79 2023 1435 1449 10.1016/j.jhep.2023.08.024 37689322
66 Huo Y. Zhou Y. Zheng J. Jin G. Tao L. Yao H. Zhang J. Sun Y. Liu Y. Hu L.-P. GJB3 promotes pancreatic cancer liver metastasis by enhancing the polarization and survival of neutrophil Front. Immunol. 13 2022 983116 10.3389/fimmu.2022.983116
67 Yajuk O. Baron M. Toker S. Zelter T. Fainsod-Levi T. Granot Z. The PD-L1/PD-1 Axis Blocks Neutrophil Cytotoxicity in Cancer Cells 10 2021 1510 10.3390/cells10061510 34203915
68 Gong Z. Li Q. Shi J. Li P. Hua L. Shultz L.D. Ren G. Immunosuppressive reprogramming of neutrophils by lung mesenchymal cells promotes breast cancer metastasis Sci. Immunol. 8 2023 eadd5204 10.1126/sciimmunol.add5204
69 Schoeps B. Eckfeld C. Prokopchuk O. Böttcher J. Häußler D. Steiger K. Demir I.E. Knolle P. Soehnlein O. Jenne D.E. TIMP1 Triggers Neutrophil Extracellular Trap Formation in Pancreatic Cancer Cancer Res. 81 2021 3568 3579 10.1158/0008-5472.CAN-20-4125 33941611
70 Jiang Z.-Z. Peng Z.-P. Liu X.-C. Guo H.-F. Zhou M.-M. Jiang D. Ning W.-R. Huang Y.-F. Zheng L. Wu Y. Neutrophil extracellular traps induce tumor metastasis through dual effects on cancer and endothelial cells OncoImmunology 11 2022 2052418 10.1080/2162402X.2022.2052418
71 Li H. Li J. Bai Z. Yan S. Li J. Collagen-induced DDR1 upregulates CXCL5 to promote neutrophil extracellular traps formation and Treg infiltration in breast cancer Int. Immunopharmacol. 120 2023 110235 10.1016/j.intimp.2023.110235
72 Li J. Xia Y. Sun B. Zheng N. Li Y. Pang X. Yang F. Zhao X. Ji Z. Yu H. Neutrophil extracellular traps induced by the hypoxic microenvironment in gastric cancer augment tumour growth Cell Commun. Signal. 21 2023 86 10.1186/s12964-023-01112-5 37127629
73 David S.S. O’Shea V.L. Kundu S. Base-excision repair of oxidative DNA damage Nature 447 2007 941 950 10.1038/nature05978 17581577
74 Butin-Israeli V. Bui T.M. Wiesolek H.L. Mascarenhas L. Lee J.J. Mehl L.C. Knutson K.R. Adam S.A. Goldman R.D. Beyder A. Neutrophil-induced genomic instability impedes resolution of inflammation and wound healing J. Clin. Invest. 129 2019 712 726 10.1172/JCI122085 30640176
75 Yang L. Liu Q. Zhang X. Liu X. Zhou B. Chen J. Huang D. Li J. Li H. Chen F. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25 Nature 583 2020 133 138 10.1038/s41586-020-2394-6 32528174
76 Adrover J.M. McDowell S.A.C. He X.-Y. Quail D.F. Egeblad M. NETworking with cancer: The bidirectional interplay between cancer and neutrophil extracellular traps Cancer Cell 41 2023 505 526 10.1016/j.ccell.2023.02.001 36827980
77 Tohme S. Yazdani H.O. Al-Khafaji A.B. Chidi A.P. Loughran P. Mowen K. Wang Y. Simmons R.L. Huang H. Tsung A. Neutrophil Extracellular Traps Promote the Development and Progression of Liver Metastases after Surgical Stress Cancer Res. 76 2016 1367 1380 10.1158/0008-5472.CAN-15-1591 26759232
78 Albrengues J. Shields M.A. Ng D. Park C.G. Ambrico A. Poindexter M.E. Upadhyay P. Uyeminami D.L. Pommier A. Küttner V. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice Science 361 2018 eaao4227 10.1126/science.aao4227
79 Jaillon S. Ponzetta A. Di Mitri D. Santoni A. Bonecchi R. Mantovani A. Neutrophil diversity and plasticity in tumour progression and therapy Nat. Rev. Cancer 20 2020 485 503 10.1038/s41568-020-0281-y 32694624
80 Stehr A.M. Wang G. Demmler R. Stemmler M.P. Krug J. Tripal P. Schmid B. Geppert C.I. Hartmann A. Muñoz L.E. Neutrophil extracellular traps drive epithelial-mesenchymal transition of human colon cancer J. Pathol. 256 2022 455 467 10.1002/path.5860 34939675
81 Deryugina E. Carré A. Ardi V. Muramatsu T. Schmidt J. Pham C. Quigley J.P. Neutrophil Elastase Facilitates Tumor Cell Intravasation and Early Metastatic Events iScience 23 2020 101799 10.1016/j.isci.2020.101799
82 Zhang Y. Wang C. Li W. Tian W. Tang C. Xue L. Lin Z. Liu G. Liu D. Zhou Y. Neutrophil Cyto-Pharmaceuticals Suppressing Tumor Metastasis via Inhibiting Hypoxia-Inducible Factor-1α in Circulating Breast Cancer Cells Adv. Healthc. Mater. 11 2022 2101761 10.1002/adhm.202101761
83 Xiong S. Dong L. Cheng L. Neutrophils in cancer carcinogenesis and metastasis J. Hematol. Oncol. 14 2021 173 10.1186/s13045-021-01187-y 34674757
84 Grisaru-Tal S. Rothenberg M.E. Munitz A. Eosinophil-lymphocyte interactions in the tumor microenvironment and cancer immunotherapy Nat. Immunol. 23 2022 1309 1316 10.1038/s41590-022-01291-2 36002647
85 Grisaru-Tal S. Itan M. Klion A.D. Munitz A. A new dawn for eosinophils in the tumour microenvironment Nat. Rev. Cancer 20 2020 594 607 10.1038/s41568-020-0283-9 32678342
86 Poto R. Gambardella A.R. Marone G. Schroeder J.T. Mattei F. Schiavoni G. Varricchi G. Basophils from allergy to cancer Front. Immunol. 13 2022 1056838 10.3389/fimmu.2022.1056838
87 Sektioglu I.M. Carretero R. Bulbuc N. Bald T. Tüting T. Rudensky A.Y. Hämmerling G.J. Basophils Promote Tumor Rejection via Chemotaxis and Infiltration of CD8+ T Cells Cancer Res. 77 2017 291 302 10.1158/0008-5472.CAN-16-0993 27879269
88 Schroeder J.T. Adeosun A.A. Do D. Bieneman A.P. Galectin-3 is essential for IgE-dependent activation of human basophils by A549 lung epithelial cells J. Allergy Clin. Immunol. 144 2019 312 315.e1 10.1016/j.jaci.2019.03.001 30857982
89 de Paulis A. Prevete N. Fiorentino I. Rossi F.W. Staibano S. Montuori N. Ragno P. Longobardi A. Liccardo B. Genovese A. Expression and functions of the vascular endothelial growth factors and their receptors in human basophils J. Immunol. 177 2006 7322 7331 10.4049/jimmunol.177.10.7322 17082651
90 Lichterman J.N. Reddy S.M. Mast Cells: A New Frontier for Cancer Immunotherapy Cells 10 2021 1270 10.3390/cells10061270 34063789
91 Nakae S. Suto H. Iikura M. Kakurai M. Sedgwick J.D. Tsai M. Galli S.J. Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF J. Immunol. 176 2006 2238 2248 10.4049/jimmunol.176.4.2238 16455980
92 Blair R.J. Meng H. Marchese M.J. Ren S. Schwartz L.B. Tonnesen M.G. Gruber B.L. Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor J. Clin. Invest. 99 1997 2691 2700 10.1172/JCI119458 9169499
93 Hegde S. Leader A.M. Merad M. MDSC: Markers, development, states, and unaddressed complexity Immunity 54 2021 875 884 10.1016/j.immuni.2021.04.004 33979585
94 Almand B. Clark J.I. Nikitina E. van Beynen J. English N.R. Knight S.C. Carbone D.P. Gabrilovich D.I. Increased Production of Immature Myeloid Cells in Cancer Patients: A Mechanism of Immunosuppression in Cancer1 J. Immunol. 166 2001 678 689 10.4049/jimmunol.166.1.678 11123353
95 Gabrilovich D.I. Bronte V. Chen S.-H. Colombo M.P. Ochoa A. Ostrand-Rosenberg S. Schreiber H. The Terminology Issue for Myeloid-Derived Suppressor Cells Cancer Res. 67 2007 425 426 10.1158/0008-5472.CAN-06-3037 17210725
96 Bronte V. Brandau S. Chen S.-H. Colombo M.P. Frey A.B. Greten T.F. Mandruzzato S. Murray P.J. Ochoa A. Ostrand-Rosenberg S. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards Nat. Commun. 7 2016 12150 10.1038/ncomms12150
97 Ai L. Mu S. Sun C. Fan F. Yan H. Qin Y. Cui G. Wang Y. Guo T. Mei H. Wang H. Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation Mol. Cancer 18 2019 1 12 10.1186/s12943-019-1011-5 30609930
98 Schouppe E. Mommer C. Movahedi K. Laoui D. Morias Y. Gysemans C. Luyckx A. De Baetselier P. Van Ginderachter J.A. Tumor-induced myeloid-derived suppressor cell subsets exert either inhibitory or stimulatory effects on distinct CD8+ T-cell activation events Eur. J. Immunol. 43 2013 2930 2942 10.1002/eji.201343349 23878002
99 Tomić S. Joksimović B. Bekić M. Vasiljević M. Milanović M. Čolić M. Vučević D. Prostaglanin-E2 Potentiates the Suppressive Functions of Human Mononuclear Myeloid-Derived Suppressor Cells and Increases Their Capacity to Expand IL-10-Producing Regulatory T Cell Subsets Front. Immunol. 10 2019 475 30936876
100 Cui T.X. Kryczek I. Zhao L. Zhao E. Kuick R. Roh M.H. Vatan L. Szeliga W. Mao Y. Thomas D.G. Myeloid-Derived Suppressor Cells Enhance Stemness of Cancer Cells by Inducing MicroRNA101 and Suppressing the Corepressor CtBP2 Immunity 39 2013 611 621 10.1016/j.immuni.2013.08.025 24012420
101 Wang Y. Yin K. Tian J. Xia X. Ma J. Tang X. Xu H. Wang S. Granulocytic Myeloid-Derived Suppressor Cells Promote the Stemness of Colorectal Cancer Cells through Exosomal S100A9 Adv. Sci. 6 2019 1901278 10.1002/advs.201901278
102 Eberl G. Colonna M. Di Santo J.P. McKenzie A.N.J. Innate lymphoid cells. Innate lymphoid cells: a new paradigm in immunology Science 348 2015 aaa6566 10.1126/science.aaa6566
103 Vivier E. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. Koyasu S. Locksley R.M. McKenzie A.N.J. Mebius R.E. Innate Lymphoid Cells: 10 Years On Cell 174 2018 1054 1066 10.1016/j.cell.2018.07.017 30142344
104 Spits H. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. Koyasu S. Locksley R.M. McKenzie A.N.J. Mebius R.E. Innate lymphoid cells--a proposal for uniform nomenclature Nat. Rev. Immunol. 13 2013 145 149 10.1038/nri3365 23348417
105 Long E.O. Kim H.S. Liu D. Peterson M.E. Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition Annu. Rev. Immunol. 31 2013 227 258 10.1146/annurev-immunol-020711-075005 23516982
106 Alfarra H. Weir J. Grieve S. Reiman T. Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy Front. Immunol. 11 2020 575609 10.3389/fimmu.2020.575609
107 Orange J.S. Formation and function of the lytic NK-cell immunological synapse Nat. Rev. Immunol. 8 2008 713 725 10.1038/nri2381 19172692
108 Voskoboinik I. Whisstock J.C. Trapani J.A. Perforin and granzymes: function, dysfunction and human pathology Nat. Rev. Immunol. 15 2015 388 400 10.1038/nri3839 25998963
109 Gwalani L.A. Orange J.S. Single Degranulations in NK Cells Can Mediate Target Cell Killing J. Immunol. 200 2018 3231 3243 10.4049/jimmunol.1701500 29592963
110 Zamai L. Ahmad M. Bennett I.M. Azzoni L. Alnemri E.S. Perussia B. Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells J. Exp. Med. 188 1998 2375 2380 10.1084/jem.188.12.2375 9858524
111 Shimasaki N. Jain A. Campana D. NK cells for cancer immunotherapy Nat. Rev. Drug Discov. 19 2020 200 218 10.1038/s41573-019-0052-1 31907401
112 Zhou Z. He H. Wang K. Shi X. Wang Y. Su Y. Wang Y. Li D. Liu W. Zhang Y. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells Science 368 2020 eaaz7548 10.1126/science.aaz7548
113 Bickett T.E. Knitz M. Darragh L.B. Bhatia S. Van Court B. Gadwa J. Bhuvane S. Piper M. Nguyen D. Tu H. FLT3L Release by Natural Killer Cells Enhances Response to Radioimmunotherapy in Preclinical Models of HNSCC Clin. Cancer Res. 27 2021 6235 6249 10.1158/1078-0432.CCR-21-0971 34518311
114 Lee J.H. Shklovskaya E. Lim S.Y. Carlino M.S. Menzies A.M. Stewart A. Pedersen B. Irvine M. Alavi S. Yang J.Y.H. Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition Nat. Commun. 11 2020 1897 10.1038/s41467-020-15726-7 32312968
115 Lee H. Da Silva I.P. Palendira U. Scolyer R.A. Long G.V. Wilmott J.S. Targeting NK Cells to Enhance Melanoma Response to Immunotherapies Cancers 13 2021 1363 10.3390/cancers13061363 33802954
116 Zhong J. Yang X. Chen J. He K. Gao X. Wu X. Zhang M. Zhou H. Xiao F. An L. Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands Nat. Commun. 13 2022 4795 10.1038/s41467-022-32311-2 35970825
117 Paczulla A.M. Rothfelder K. Raffel S. Konantz M. Steinbacher J. Wang H. Tandler C. Mbarga M. Schaefer T. Falcone M. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion Nature 572 2019 254 259 10.1038/s41586-019-1410-1 31316209
118 Zheng X. Hou Z. Qian Y. Zhang Y. Cui Q. Wang X. Shen Y. Liu Z. Zhou Y. Fu B. Tumors evade immune cytotoxicity by altering the surface topology of NK cells Nat. Immunol. 24 2023 802 813 10.1038/s41590-023-01462-9 36959292
119 Zheng X. Qian Y. Fu B. Jiao D. Jiang Y. Chen P. Shen Y. Zhang H. Sun R. Tian Z. Wei H. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance Nat. Immunol. 20 2019 1656 1667 10.1038/s41590-019-0511-1 31636463
120 Moral J.A. Leung J. Rojas L.A. Ruan J. Zhao J. Sethna Z. Ramnarain A. Gasmi B. Gururajan M. Redmond D. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity Nature 579 2020 130 135 10.1038/s41586-020-2015-4 32076273
121 Schuijs M.J. Png S. Richard A.C. Tsyben A. Hamm G. Stockis J. Garcia C. Pinaud S. Nicholls A. Ros X.R. ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung Nat. Immunol. 21 2020 998 1009 10.1038/s41590-020-0745-y 32747815
122 Jacquelot N. Seillet C. Wang M. Pizzolla A. Liao Y. Hediyeh-Zadeh S. Grisaru-Tal S. Louis C. Huang Q. Schreuder J. Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma Nat. Immunol. 22 2021 851 864 10.1038/s41590-021-00943-z 34099918
123 Ye L. Jin K. Liao Z. Xiao Z. Xu H. Lin X. Li H. Li T. Zhang W. Han X. Hypoxia-reprogrammed regulatory group 2 innate lymphoid cells promote immunosuppression in pancreatic cancer EBioMedicine 79 2022 104016 10.1016/j.ebiom.2022.104016
124 Irshad S. Flores-Borja F. Lawler K. Monypenny J. Evans R. Male V. Gordon P. Cheung A. Gazinska P. Noor F. RORγt+ Innate Lymphoid Cells Promote Lymph Node Metastasis of Breast Cancers Cancer Res. 77 2017 1083 1096 10.1158/0008-5472.CAN-16-0598 28082403
125 Singh A. Sharma A. Lymphoid tissue inducer cells in cancer: a potential therapeutic target Mol. Cell. Biochem. 478 2023 2789 2794 10.1007/s11010-023-04699-y 36922480
126 Goc J. Lv M. Bessman N.J. Flamar A.-L. Sahota S. Suzuki H. Teng F. Putzel G.G. JRI Live Cell BankEberl G. Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer Cell 184 2021 5015 5030.e16 10.1016/j.cell.2021.07.029 34407392
127 Nussbaum K. Burkhard S.H. Ohs I. Mair F. Klose C.S.N. Arnold S.J. Diefenbach A. Tugues S. Becher B. Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs J. Exp. Med. 214 2017 2331 2347 10.1084/jem.20162031 28698286
128 Liu Y. Song Y. Lin D. Lei L. Mei Y. Jin Z. Gong H. Zhu Y. Hu B. Zhang Y. NCR- group 3 innate lymphoid cells orchestrate IL-23/IL-17 axis to promote hepatocellular carcinoma development EBioMedicine 41 2019 333 344 10.1016/j.ebiom.2019.02.050 30827928
129 Xuan X. Zhou J. Tian Z. Lin Y. Song J. Ruan Z. Ni B. Zhao H. Yang W. ILC3 cells promote the proliferation and invasion of pancreatic cancer cells through IL-22/AKT signaling Clin. Transl. Oncol. 22 2020 563 575 10.1007/s12094-019-02160-5 31203574
130 Ruf B. Greten T.F. Korangy F. Innate lymphoid cells and innate-like T cells in cancer - at the crossroads of innate and adaptive immunity Nat. Rev. Cancer 23 2023 351 371 10.1038/s41568-023-00562-w 37081117
131 Bendelac A. Lantz O. Quimby M.E. Yewdell J.W. Bennink J.R. Brutkiewicz R.R. CD1 recognition by mouse NK1+ T lymphocytes Science 268 1995 863 865 10.1126/science.7538697 7538697
132 Eckle S.B.G. Corbett A.J. Keller A.N. Chen Z. Godfrey D.I. Liu L. Mak J.Y.W. Fairlie D.P. Rossjohn J. McCluskey J. Recognition of Vitamin B Precursors and Byproducts by Mucosal Associated Invariant T Cells J. Biol. Chem. 290 2015 30204 30211 10.1074/jbc.R115.685990 26468291
133 Ruf B. Catania V.V. Wabitsch S. Ma C. Diggs L.P. Zhang Q. Heinrich B. Subramanyam V. Cui L.L. Pouzolles M. Activating Mucosal-Associated Invariant T Cells Induces a Broad Antitumor Response Cancer Immunol. Res. 9 2021 1024 1034 10.1158/2326-6066.CIR-20-0925 34193462
134 Correia D.V. Lopes A. Silva-Santos B. Tumor cell recognition by γδ T lymphocytes: T-cell receptor vs. NK-cell receptors OncoImmunology 2 2013 e22892 10.4161/onci.22892
135 Wakita D. Sumida K. Iwakura Y. Nishikawa H. Ohkuri T. Chamoto K. Kitamura H. Nishimura T. Tumor-infiltrating IL-17-producing gammadelta T cells support the progression of tumor by promoting angiogenesis Eur. J. Immunol. 40 2010 1927 1937 10.1002/eji.200940157 20397212
136 Batlle E. Massagué J. Transforming Growth Factor-β Signaling in Immunity and Cancer Immunity 50 2019 924 940 10.1016/j.immuni.2019.03.024 30995507
137 Bagchi S. Yuan R. Engleman E.G. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance Annu. Rev. Pathol. 16 2021 223 249 10.1146/annurev-pathol-042020-042741 33197221
138 Mellman I. Coukos G. Dranoff G. Cancer immunotherapy comes of age Nature 480 2011 480 489 10.1038/nature10673 22193102
139 Cai L. Li Y. Tan J. Xu L. Li Y. Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy J. Hematol. Oncol. 16 2023 101 10.1186/s13045-023-01499-1 37670328
140 Andrews L.P. Marciscano A.E. Drake C.G. Vignali D.A.A. LAG3 (CD223) as a cancer immunotherapy target Immunol. Rev. 276 2017 80 96 10.1111/imr.12519 28258692
141 Takizawa F. Hashimoto K. Miyazawa R. Ohta Y. Veríssimo A. Flajnik M.F. Parra D. Tokunaga K. Suetake H. Sunyer J.O. Dijkstra J.M. CD4 and LAG-3 from sharks to humans: related molecules with motifs for opposing functions Front. Immunol. 14 2023 1267743 10.3389/fimmu.2023.1267743
142 Grosso J.F. Kelleher C.C. Harris T.J. Maris C.H. Hipkiss E.L. De Marzo A. Anders R. Netto G. Getnet D. Bruno T.C. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems J. Clin. Invest. 117 2007 3383 3392 10.1172/JCI31184 17932562
143 Huo J.-L. Wang Y.-T. Fu W.-J. Lu N. Liu Z.-S. The promising immune checkpoint LAG-3 in cancer immunotherapy: from basic research to clinical application Front. Immunol. 13 2022 956090 10.3389/fimmu.2022.956090
144 Castelli C. Triebel F. Rivoltini L. Camisaschi C. Lymphocyte activation gene-3 (LAG-3, CD223) in plasmacytoid dendritic cells (pDCs): a molecular target for the restoration of active antitumor immunity OncoImmunology 3 2014 e967146 10.4161/21624011.2014.967146
145 Tawbi H.A. Schadendorf D. Lipson E.J. Ascierto P.A. Matamala L. Castillo Gutiérrez E. Rutkowski P. Gogas H.J. Lao C.D. De Menezes J.J. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma N. Engl. J. Med. 386 2022 24 34 10.1056/NEJMoa2109970 34986285
146 Ascierto P.A. Lipson E.J. Dummer R. Larkin J. Long G.V. Sanborn R.E. Chiarion-Sileni V. Dréno B. Dalle S. Schadendorf D. Nivolumab and Relatlimab in Patients With Advanced Melanoma That Had Progressed on Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy: Results From the Phase I/IIa RELATIVITY-020 Trial J. Clin. Oncol. 41 2023 2724 2735 10.1200/JCO.22.02072 36780608
147 Wolf Y. Anderson A.C. Kuchroo V.K. TIM3 comes of age as an inhibitory receptor Nat. Rev. Immunol. 20 2020 173 185 10.1038/s41577-019-0224-6 31676858
148 Falchook G.S. Ribas A. Davar D. Eroglu Z. Wang J.S. Luke J.J. Hamilton E.P. Di Pace B. Wang T. Ghosh S. Phase 1 trial of TIM-3 inhibitor cobolimab monotherapy and in combination with PD-1 inhibitors nivolumab or dostarlimab (AMBER) J. Clin. Oncol. 40 2022 2504 10.1200/JCO.2022.40.16_suppl.2504
149 Zhang P. Liu X. Gu Z. Jiang Z. Zhao S. Song Y. Yu J. Targeting TIGIT for cancer immunotherapy: recent advances and future directions Biomark. Res. 12 2024 7 10.1186/s40364-023-00543-z 38229100
150 Gur C. Ibrahim Y. Isaacson B. Yamin R. Abed J. Gamliel M. Enk J. Bar-On Y. Stanietsky-Kaynan N. Coppenhagen-Glazer S. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack Immunity 42 2015 344 355 10.1016/j.immuni.2015.01.010 25680274
151 Demaria O. Cornen S. Daëron M. Morel Y. Medzhitov R. Vivier E. Harnessing innate immunity in cancer therapy Nature 574 2019 45 56 10.1038/s41586-019-1593-5 31578484
152 Yu L. Liu X. Wang X. Yan F. Wang P. Jiang Y. Du J. Yang Z. TIGIT+ TIM-3+ NK cells are correlated with NK cell exhaustion and disease progression in patients with hepatitis B virus-related hepatocellular carcinoma OncoImmunology 10 2021 1942673 10.1080/2162402X.2021.1942673
153 Ostroumov D. Duong S. Wingerath J. Woller N. Manns M.P. Timrott K. Kleine M. Ramackers W. Roessler S. Nahnsen S. Transcriptome Profiling Identifies TIGIT as a Marker of T-Cell Exhaustion in Liver Cancer Hepatology 73 2021 1399 1418 10.1002/hep.31466 32716559
154 Liu L. Wang A. Liu X. Han S. Sun Y. Zhang J. Guo L. Zhang Y. Blocking TIGIT/CD155 signalling reverses CD8+ T cell exhaustion and enhances the antitumor activity in cervical cancer J. Transl. Med. 20 2022 280 10.1186/s12967-022-03480-x 35729552
155 Shao Q. Wang L. Yuan M. Jin X. Chen Z. Wu C. TIGIT Induces (CD3+) T Cell Dysfunction in Colorectal Cancer by Inhibiting Glucose Metabolism Front. Immunol. 12 2021 688961 10.3389/fimmu.2021.688961
156 Cho B.C. Abreu D.R. Hussein M. Cobo M. Patel A.J. Secen N. Lee K.H. Massuti B. Hiret S. Yang J.C.H. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study Lancet Oncol. 23 2022 781 792 10.1016/S1470-2045(22)00226-1 35576957
157 Niu J. Maurice-Dror C. Lee D.H. Kim D.-W. Nagrial A. Voskoboynik M. Chung H.C. Mileham K. Vaishampayan U. Rasco D. First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer Ann. Oncol. 33 2022 169 180 10.1016/j.annonc.2021.11.002 34800678
158 Recondo G. Mezquita L. Tiragolumab and atezolizumab in patients with PD-L1 positive non-small-cell lung cancer Lancet Oncol. 23 2022 695 697 10.1016/S1470-2045(22)00261-3 35654050
159 Frentzas S. Kao S. Gao R. Zheng H. Rizwan A. Budha N. de la Hoz Pedroza L. Tan W. Meniawy T. AdvanTIG-105: a phase I dose escalation study of the anti-TIGIT monoclonal antibody ociperlimab in combination with tislelizumab in patients with advanced solid tumors J. Immunother. Cancer 11 2023 e005829 10.1136/jitc-2022-005829
160 Carretero M. Cantoni C. Bellón T. Bottino C. Biassoni R. Rodríguez A. Pérez-Villar J.J. Moretta L. Moretta A. López-Botet M. The CD94 and NKG2-A C-type lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules Eur. J. Immunol. 27 1997 563 567 10.1002/eji.1830270230 9045931
161 Braud V.M. Allan D.S. O’Callaghan C.A. Söderström K. D’Andrea A. Ogg G.S. Lazetic S. Young N.T. Bell J.I. Phillips J.H. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C Nature 391 1998 795 799 10.1038/35869 9486650
162 Le Dréan E. Vély F. Olcese L. Cambiaggi A. Guia S. Krystal G. Gervois N. Moretta A. Jotereau F. Vivier E. Inhibition of antigen-induced T cell response and antibody-induced NK cell cytotoxicity by NKG2A: association of NKG2A with SHP-1 and SHP-2 protein-tyrosine phosphatases Eur. J. Immunol. 28 1998 264 276 10.1002/(SICI)1521-4141(199801)28:01<264::AID-IMMU264>3.0.CO;2-O 9485206
163 van Hall T. André P. Horowitz A. Ruan D.F. Borst L. Zerbib R. Narni-Mancinelli E. van der Burg S.H. Vivier E. Monalizumab: inhibiting the novel immune checkpoint NKG2A J. Immunother. Cancer 7 2019 263 10.1186/s40425-019-0761-3 31623687
164 André P. Denis C. Soulas C. Bourbon-Caillet C. Lopez J. Arnoux T. Bléry M. Bonnafous C. Gauthier L. Morel A. Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells Cell 175 2018 1731 1743.e13 10.1016/j.cell.2018.10.014 30503213
165 van Duijn A. Van der Burg S.H. Scheeren F.A. CD47/SIRPα axis: bridging innate and adaptive immunity J. Immunother. Cancer 10 2022 e004589 10.1136/jitc-2022-004589
166 Yu J. Li S. Chen D. Liu D. Guo H. Yang C. Zhang W. Zhang L. Zhao G. Tu X. Crystal Structure of Human CD47 in Complex with Engineered SIRPα.D1(N80A) Molecules 27 2022 5574 10.3390/molecules27175574 36080360
167 Yang H. Xun Y. You H. The landscape overview of CD47-based immunotherapy for hematological malignancies Biomark. Res. 11 2023 15 10.1186/s40364-023-00456-x 36726125
168 Maude S.L. Laetsch T.W. Buechner J. Rives S. Boyer M. Bittencourt H. Bader P. Verneris M.R. Stefanski H.E. Myers G.D. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia N. Engl. J. Med. 378 2018 439 448 10.1056/NEJMoa1709866 29385370
169 O’Leary M.C. Lu X. Huang Y. Lin X. Mahmood I. Przepiorka D. Gavin D. Lee S. Liu K. George B. FDA Approval Summary: Tisagenlecleucel for Treatment of Patients with Relapsed or Refractory B-cell Precursor Acute Lymphoblastic Leukemia Clin. Cancer Res. 25 2019 1142 1146 10.1158/1078-0432.CCR-18-2035 30309857
170 Schubert M.-L. Schmitt M. Wang L. Ramos C.A. Jordan K. Müller-Tidow C. Dreger P. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy Ann. Oncol. 32 2021 34 48 10.1016/j.annonc.2020.10.478 33098993
171 Laskowski T.J. Biederstädt A. Rezvani K. Natural killer cells in antitumour adoptive cell immunotherapy Nat. Rev. Cancer 22 2022 557 575 10.1038/s41568-022-00491-0 35879429
172 Pan K. Farrukh H. Chittepu V.C.S.R. Xu H. Pan C.X. Zhu Z. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy J. Exp. Clin. Cancer Res. 41 2022 119 10.1186/s13046-022-02327-z 35361234
173 Dagher O.K. Posey A.D. Forks in the road for CAR T and CAR NK cell cancer therapies Nat. Immunol. 24 2023 1994 2007 10.1038/s41590-023-01659-y 38012406
174 Chin E.N. Sulpizio A. Lairson L.L. Targeting STING to promote antitumor immunity Trends Cell Biol. 33 2023 189 203 10.1016/j.tcb.2022.06.010 35931610
175 Li A. Yi M. Qin S. Song Y. Chu Q. Wu K. Activating cGAS-STING pathway for the optimal effect of cancer immunotherapy J. Hematol. Oncol. 12 2019 35 10.1186/s13045-019-0721-x 30935414
176 Decout A. Katz J.D. Venkatraman S. Ablasser A. The cGAS-STING pathway as a therapeutic target in inflammatory diseases Nat. Rev. Immunol. 21 2021 548 569 10.1038/s41577-021-00524-z 33833439
177 Lv M. Chen M. Zhang R. Zhang W. Wang C. Zhang Y. Wei X. Guan Y. Liu J. Feng K. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy Cell Res. 30 2020 966 979 10.1038/s41422-020-00395-4 32839553
178 Vonderheide R.H. Prospect of targeting the CD40 pathway for cancer therapy Clin. Cancer Res. 13 2007 1083 1088 10.1158/1078-0432.CCR-06-1893 17317815
179 Zhou Y. Richmond A. Yan C. Harnessing the potential of CD40 agonism in cancer therapy Cytokine Growth Factor Rev. 75 2024 40 56 10.1016/j.cytogfr.2023.11.002 38102001
180 Tay N.Q. Lee D.C.P. Chua Y.L. Prabhu N. Gascoigne N.R.J. Kemeny D.M. CD40L Expression Allows CD8+ T Cells to Promote Their Own Expansion and Differentiation through Dendritic Cells Front. Immunol. 8 2017 1484 10.3389/fimmu.2017.01484
181 Tong A.W. Stone M.J. Prospects for CD40-directed experimental therapy of human cancer Cancer Gene Ther. 10 2003 1 13 10.1038/sj.cgt.7700527 12489023
182 Yan C. Saleh N. Yang J. Nebhan C.A. Vilgelm A.E. Reddy E.P. Roland J.T. Johnson D.B. Chen S.-C. Shattuck-Brandt R.L. Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade Mol. Cancer 20 2021 85 10.1186/s12943-021-01366-y 34092233
183 Macatonia S.E. Hosken N.A. Litton M. Vieira P. Hsieh C.S. Culpepper J.A. Wysocka M. Trinchieri G. Murphy K.M. O’Garra A. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells J. Immunol. 154 1995 5071 5079 7730613
184 Buhtoiarov I.N. Lum H. Berke G. Paulnock D.M. Sondel P.M. Rakhmilevich A.L. CD40 ligation activates murine macrophages via an IFN-gamma-dependent mechanism resulting in tumor cell destruction in vitro J. Immunol. 174 2005 6013 6022 10.4049/jimmunol.174.10.6013 15879094
185 Byrne K.T. Betts C.B. Mick R. Sivagnanam S. Bajor D.L. Laheru D.A. Chiorean E.G. O’Hara M.H. Liudahl S.M. Newcomb C. Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer Clin. Cancer Res. 27 2021 4574 4586 10.1158/1078-0432.CCR-21-1047 34112709
186 Combes F. Meyer E. Sanders N.N. Immune cells as tumor drug delivery vehicles J. Control. Release 327 2020 70 87 10.1016/j.jconrel.2020.07.043 32735878
187 Cao H. Dan Z. He X. Zhang Z. Yu H. Yin Q. Li Y. Liposomes Coated with Isolated Macrophage Membrane Can Target Lung Metastasis of Breast Cancer ACS Nano 10 2016 7738 7748 10.1021/acsnano.6b03148 27454827
188 Xia Y. Rao L. Yao H. Wang Z. Ning P. Chen X. Engineering Macrophages for Cancer Immunotherapy and Drug Delivery Adv. Mater. 32 2020 e2002054 10.1002/adma.202002054
189 Choi J. Kim H.-Y. Ju E.J. Jung J. Park J. Chung H.-K. Lee J.S. Lee J.S. Park H.J. Song S.Y. Use of macrophages to deliver therapeutic and imaging contrast agents to tumors Biomaterials 33 2012 4195 4203 10.1016/j.biomaterials.2012.02.022 22398206
190 Chu Y. Luo Y. Su B. Li C. Guo Q. Zhang Y. Liu P. Chen H. Zhao Z. Zhou Z. A neutrophil-biomimic platform for eradicating metastatic breast cancer stem-like cells by redox microenvironment modulation and hypoxia-triggered differentiation therapy Acta Pharm. Sin. B 13 2023 298 314 10.1016/j.apsb.2022.05.027 36815033
191 Zhang J. Ji C. Zhang H. Shi H. Mao F. Qian H. Xu W. Wang D. Pan J. Fang X. Engineered neutrophil-derived exosome-like vesicles for targeted cancer therapy Sci. Adv. 8 2022 eabj8207 10.1126/sciadv.abj8207
192 Chang Y. Cai X. Syahirah R. Yao Y. Xu Y. Jin G. Bhute V.J. Torregrosa-Allen S. Elzey B.D. Won Y.-Y. CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy Nat. Commun. 14 2023 2266 10.1038/s41467-023-37872-4 37080958
193 Shields C.W. Evans M.A. Wang L.L.-W. Baugh N. Iyer S. Wu D. Zhao Z. Pusuluri A. Ukidve A. Pan D.C. Mitragotri S. Cellular backpacks for macrophage immunotherapy Sci. Adv. 6 2020 eaaz6579 10.1126/sciadv.aaz6579
194 Kapate N. Dunne M. Gottlieb A.P. Mukherji M. Suja V.C. Prakash S. Park K.S. Kumbhojkar N. Guerriero J.L. Mitragotri S. Polymer Backpack-Loaded Tissue Infiltrating Monocytes for Treating Cancer Adv. Healthc. Mater. 6 2024 e2304144 10.1002/adhm.202304144
195 An J.-X. Han Z.-Y. Qin Y.-T. Li C.-X. He J.-L. Zhang X.-Z. Bacteria-Based Backpacks to Enhance Adoptive Macrophage Transfer against Solid Tumors Adv. Mater. 36 2024 e2305384 10.1002/adma.202305384
196 Andreesen R. Scheibenbogen C. Brugger W. Krause S. Meerpohl H.G. Leser H.G. Engler H. Löhr G.W. Adoptive transfer of tumor cytotoxic macrophages generated in vitro from circulating blood monocytes: a new approach to cancer immunotherapy Cancer Res. 50 1990 7450 7456 1701343
197 Dumont S. Hartmann D. Poindron P. Oberling F. Faradji A. Bartholeyns J. Control of the antitumoral activity of human macrophages produced in large amounts in view of adoptive transfer Eur. J. Cancer Clin. Oncol. 24 1988 1691 1698 10.1016/0277-5379(88)90069-7 3208813
198 Ritchie D. Mileshkin L. Wall D. Bartholeyns J. Thompson M. Coverdale J. Lau E. Wong J. Eu P. Hicks R.J. Prince H.M. In vivo tracking of macrophage activated killer cells to sites of metastatic ovarian carcinoma Cancer Immunol. Immunother. 56 2007 155 163 10.1007/s00262-006-0181-3 16733671
199 Gu Y.-Z. Zhao X. Song X.-R. Ex vivo pulsed dendritic cell vaccination against cancer Acta Pharmacol. Sin. 41 2020 959 969 10.1038/s41401-020-0415-5 32366940
200 Elliott L.A. Doherty G.A. Sheahan K. Ryan E.J. Human Tumor-Infiltrating Myeloid Cells: Phenotypic and Functional Diversity Front. Immunol. 8 2017 86 10.3389/fimmu.2017.00086 28220123
201 Giese M.A. Hind L.E. Huttenlocher A. Neutrophil plasticity in the tumor microenvironment Blood 133 2019 2159 2167 10.1182/blood-2018-11-844548 30898857
202 Nishida-Aoki N. Gujral T.S. Emerging approaches to study cell-cell interactions in tumor microenvironment Oncotarget 10 2019 785 797 10.18632/oncotarget.26585 30774780
203 Neal J.T. Kuo C.J. Organoids as Models for Neoplastic Transformation Annu. Rev. Pathol. 11 2016 199 220 10.1146/annurev-pathol-012615-044249 26907527
204 Gutbier S. Wanke F. Dahm N. Rümmelin A. Zimmermann S. Christensen K. Köchl F. Rautanen A. Hatje K. Geering B. Large-Scale Production of Human iPSC-Derived Macrophages for Drug Screening Int. J. Mol. Sci. 21 2020 4808 10.3390/ijms21134808 32645954
205 Shen J. Lyu S. Xu Y. Zhang S. Li L. Li J. Mou J. Xie L. Tang K. Wen W. Activating innate immune responses repolarizes hPSC-derived CAR macrophages to improve anti-tumor activity Cell Stem Cell 31 2024 1003 1019.e9 10.1016/j.stem.2024.04.012 38723634
206 Goldenson B.H. Hor P. Kaufman D.S. iPSC-Derived Natural Killer Cell Therapies - Expansion and Targeting Front. Immunol. 13 2022 841107 10.3389/fimmu.2022.841107
207 Senju S. Haruta M. Matsumura K. Matsunaga Y. Fukushima S. Ikeda T. Takamatsu K. Irie A. Nishimura Y. Generation of dendritic cells and macrophages from human induced pluripotent stem cells aiming at cell therapy Gene Ther. 18 2011 874 883 10.1038/gt.2011.22 21430784
208 Zhu H. Blum R.H. Bjordahl R. Gaidarova S. Rogers P. Lee T.T. Abujarour R. Bonello G.B. Wu J. Tsai P.-F. Pluripotent stem cell-derived NK cells with high-affinity noncleavable CD16a mediate improved antitumor activity Blood 135 2020 399 410 10.1182/blood.2019000621 31856277
209 Miyashita A. Fukushima S. Nakahara S. Kubo Y. Tokuzumi A. Yamashita J. Aoi J. Haruta M. Senju S. Nishimura Y. Immunotherapy against Metastatic Melanoma with Human iPS Cell-Derived Myeloid Cell Lines Producing Type I Interferons Cancer Immunol. Res. 4 2016 248 258 10.1158/2326-6066.CIR-15-0096 26714554
210 Xue D. Lu S. Zhang H. Zhang L. Dai Z. Kaufman D.S. Zhang J. Induced pluripotent stem cell-derived engineered T cells, natural killer cells, macrophages, and dendritic cells in immunotherapy Trends Biotechnol. 41 2023 907 922 10.1016/j.tibtech.2023.02.003 36858941
211 Li Y. Hermanson D.L. Moriarity B.S. Kaufman D.S. Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity Cell Stem Cell 23 2018 181 192.e5 10.1016/j.stem.2018.06.002 30082067
212 Zhang L. Tian L. Dai X. Yu H. Wang J. Lei A. Zhu M. Xu J. Zhao W. Zhu Y. Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions J. Hematol. Oncol. 13 2020 153 10.1186/s13045-020-00983-2 33176869
213 Tominaga S. Ojima T. Miyazawa M. Iwamoto H. Kitadani J. Maruoka S. Hayata K. Yamaue H. Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system Gene Ther. 30 2023 552 559 10.1038/s41434-023-00388-z 36959396
