Tumor immune checkpoints and their associated inhibitors

Tumor immune checkpoints and their associated inhibitors 肿瘤免疫检查点及与其相关抑制剂 1 2 3 4 equal first-author 1 2 3 equal 1 2 3 1 2 3 1 2 3 5 6 7 corresp Aifu LIN, linaifu@zju.edu.cn Aifu LIN, linaifu@zju.edu.cn linaifu@zju.edu.cn https://orcid.org/0000-0002-3968-3617 MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China 浙江大学生命科学学院生命系统稳态与保护教育部重点实验室，中国杭州市，310058 浙江大学生命科学学院生命系统稳态与保护教育部重点实验室，中国杭州市，310058 Cancer Center, Zhejiang University, Hangzhou 310058, China Cancer Center, Zhejiang University, Hangzhou 310058, China 浙江大学癌症研究中心，中国杭州市，310058 浙江大学癌症研究中心，中国杭州市，310058 Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, China 浙江省细胞与基因工程重点实验室，中国杭州市，310058 浙江省细胞与基因工程重点实验室，中国杭州市，310058 Chu Kochen Honors College of Zhejiang University, Hangzhou 310058, China Chu Kochen Honors College of Zhejiang University, Hangzhou 310058, China 浙江大学竺可桢荣誉学院，中国杭州市，310058 浙江大学竺可桢荣誉学院，中国杭州市，310058 Breast Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China Breast Center of the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China 浙江大学医学院附属第一医院乳腺疾病诊治中心，中国杭州市，310058 浙江大学医学院附属第一医院乳腺疾病诊治中心，中国杭州市，310058 International School of Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China International School of Medicine, International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu 322000, China 浙江大学医学院第四附属医院国际医学院，中国义乌市，322000 浙江大学医学院第四附属医院国际医学院，中国义乌市，322000 ZJU-QILU Joint Research Institute, Hangzhou 310058, China ZJU-QILU Joint Research Institute, Hangzhou 310058, China 浙江大学-齐鲁制药联合研究院，中国杭州市，310058 浙江大学-齐鲁制药联合研究院，中国杭州市，310058 Immunological evasion is one of the defining characteristics of cancers, as the immune modification of an immune checkpoint (IC) confers immune evasion capabilities to tumor cells. Multiple ICs, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can bind to their respective receptors and reduce tumor immunity in a variety of ways, including blocking immune cell activation signals. IC blockade (ICB) therapies targeting these checkpoint molecules have demonstrated significant clinical benefits. This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers. Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment. In this review, we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels, including epigenetic regulation, transcriptional regulation, and post-translational modifications. In addition, we provide a summary of the medications targeting various nodes in the regulatory pathway, and highlight the potential of newly identified IC molecules, focusing on their potential implications for cancer diagnostics and immunotherapy. 包括程序性细胞死亡蛋白1（PD-1）和细胞毒性T淋巴细胞相关抗原4（CTLA-4）在内的免疫检查点蛋白，可以与各自的受体结合，以阻断免疫细胞的激活信号等方式促进肿瘤细胞免疫逃逸。这种由免疫检查点的免疫修饰赋予的肿瘤细胞免疫规避能力，使得免疫逃逸成为肿瘤的重要特征之一。靶向上述分子的免疫检查点阻断（ICB）疗法通过抗体与特定小分子抑制剂抑制肿瘤关键信号通路，破解肿瘤患者的免疫耐受，已表现出优异的临床效益。因此，破译这些免疫检查点分子的作用和调节机制将为临床治疗提供关键的理论指导。在这篇综述中，我们总结了目前关于这些免疫检查点分子在多个层面上的功能和调节机制，包括表观遗传调节、转录调节和翻译后修饰。此外，我们还对针对调控途径中各个节点的药物进行了总结，进一步阐明新鉴定的免疫检查点分子的临床潜力，重点介绍了它们对癌症诊断和免疫治疗的潜在意义。 Immune checkpoint Immune checkpoint inhibitor Programmed cell death-ligand 1 (PD-L1) Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) Lymphocyte activation gene-3 (LAG-3) T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) B7 family 免疫检查点 免疫检查点抑制剂 PD-L1 CTLA-4 LAG-3 TIGIT B7家族 1 Introduction 1 Interactions between the immune system and tumors are regulated by a complex network of biological modulators. Tumor cells can develop the ability to evade immune surveillance through immune editing, in which immune checkpoints (ICs) play an important role ( Schreiber et al., 2011 Schreiber et al., 2011 ). ICs are molecules expressed on the surfaces of immune cells, regulating the immune response. Their normal function is to control immune homeostasis ( Pardoll, 2012 Pardoll, 2012 ). However, the tumor activates ICs through ligands to suppress T-cell function and develop the ability to circumvent immune recognition and evade immune response. Thus, tumor cells are supported by these ICs in the tumor microenvironment (TME) to inactivate tumor-infiltrating immune cells and achieve immune tolerance ( Fig. 1 Fig. 1 ) ( Topalian et al., 2016 Topalian et al., 2016 ). The main idea of tumor immunotherapy is to reactivate the immune cells in the TME by blocking the immune suppressive effect of cancer cells ( Fig.1 Fig.1 ), leading to their destruction, eventually achieving the goal of oncology treatments and preventing tumor recurrence. Immunotherapy is a revolutionary innovation in cancer treatment, that has completely transformed oncology ( Zhang and Zhang, 2020 Zhang and Zhang, 2020 ). It provides several advantages over traditional chemotherapy and targeted medicines, including more flexibility, higher long-term survival rate, and fewer side effects ( Tan et al., 2020 Tan et al., 2020 ). In spite of tremendous advances in immunotherapies, several obstacles exist, like the restricted response rates, the inability to forecast clinical efficacy, and the possibility of side effects, which cannot be overlooked ( Hegde and Chen, 2020 Hegde and Chen, 2020 ). The most notable advanced technique is IC blockade (ICB) therapy. ICB refers to the targeting of IC molecules by blocking their recognition of ligands or inhibiting their expression on tumor cells by IC inhibitors (ICIs). ICIs block this process in several ways to reactivate suppressed T-cells and enhance antitumor immunity ( Clarke et al., 2018 Clarke et al., 2018 ). Over the past few years, numerous clinical trials of checkpoint blockade in the lung, prostate, kidney, and other types of cancer have shown promising results, highlighting the great potential of this therapeutic strategy ( Sharon et al., 2014 Sharon et al., 2014 ) and promoting ICIs as one of the most potent therapeutic options in tumors ( Robert, 2020 Robert, 2020 ). As classical IC molecules, programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) have garnered tremendous interest in the field of oncology ( Robert, 2020 Robert, 2020 ). As demonstrated in these clinical studies, the blockade of different ICs activates the antitumor immune response of the immune system through different mechanisms and at various levels, which has transformed cancer therapeutics. Therefore, it is essential to consider the functions of inhibitors of numerous ICs. The clinical efficacy results of antibodies that inhibit receptors suggest that antitumor immunity can be enhanced on multiple levels, and that combinatorial methods can be rationally designed using molecular considerations and preclinical models ( Pandey et al., 2022 Pandey et al., 2022 ). Based on the discovery of ICs and the success of checkpoint blockade inhibitors, the new generation of tumor immunotherapies has recently entered the mainstream strategies of cancer treatment. However, some patients exhibit low response to these therapies, which could be attributed to the expression of ICs in the TME ( Topalian et al., 2020 Topalian et al., 2020 ). Therefore, it is of considerable clinical and scientific importance to understand the molecular mechanisms behind the control of ICs and create novel techniques, such as combining ICI with other medications, or devising new immunotherapies for broader, more durable response and safer efficacy. 2 Classical IC molecules 1 2.1 PD-L1/PD-1 2 PD-1, also known as cluster of differentiation 279 (CD279), belongs to the CD28 superfamily and is a receptor protein expressed on the surface of immune cells. It is expressed at low levels on resting cells of the immune system and can also be expressed on activated T-cells, B-cells, natural killer (NK) cells, monocytes, dendritic cells (DCs), and tumor-infiltrating lymphocytes (TILs) ( Table 1 Table 1 ) ( Agata et al., 1996 Agata et al., 1996 ; Norris et al., 2012 Norris et al., 2012 ; Thibult et al., 2013 Thibult et al., 2013 ; Gros et al., 2014 Gros et al., 2014 ; Lim TS et al., 2016 Lim TS et al., 2016 ; Jiang, 2020 Jiang, 2020 ). When PD-1 interacts with its ligands, the tyrosine residues of cytoplasmic immunoreceptors on T-cells will be phosphorylated and protein tyrosine phosphatases, including SH2-containing protein tyrosine phosphatase 1 (SHP1) and SHP2, will be recruited, thereby inhibiting co-stimulatory receptors such as the T-cell receptor (TCR) and CD28. This results in the dephosphorylation of key downstream kinases ( Boussiotis, 2016 Boussiotis, 2016 ; Borst et al., 2021 Borst et al., 2021 ), which counteracts activation signals induced by TCR-CD28 and inhibits the activation, proliferation, and cytokine production, and even the survival of T-cells ( Boussiotis, 2016 Boussiotis, 2016 ). The ligands of PD-1, PD-L1 and PD-L2, can be expressed in a range of cell types, including antigen-presenting cells (APCs) and cancer cells, where the PD-L1/PD-1 axis is associated with immuno-inflammatory phenotypes ( Cesano and Warren, 2018 Cesano and Warren, 2018 ) and is involved in the immune escape of cancer cells ( Wei et al., 2018 Wei et al., 2018 ). PD-L1, also known as CD274 and B7-H1, belongs to the B7 family and is highly expressed in melanoma, lung cancer, ovarian cancer, colon cancer, and many other human cancer tissues ( Skafi et al., 2020 Skafi et al., 2020 ). The overexpression of PD-L1 is closely related to poor clinical prognosis, and various regulatory factors and drugs can affect PD-L1 expression directly or indirectly at the DNA, RNA, and protein levels ( Fig.2 Fig.2 ) ( Wu Q et al., 2021 Wu Q et al., 2021 ; Xiong et al., 2021 Xiong et al., 2021 ; Yi et al., 2021 Yi et al., 2021 ; Yamaguchi et al., 2022 Yamaguchi et al., 2022 ). PD-1: programmed cell death protein-1; PD-L1: programmed cell death-ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated antigen-4; LAG-3: lymphocyte activation gene-3; TIGIT: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain; B7-H3: B7 homolog 3 protein; VISTA: immunoglobulin V structural domain-containing T-cell activation suppressor; HHLA2: human endogenous retroviral H long terminal repeat-binding protein 2; NK: natural killer; DCs: dendritic cells; TILs: tumor-infiltrating lymphocytes; CD: cluster of differentiation; Treg: regulatory T; CRC: colorectal cancer. Checkpoint Cells PD-1 Activated T-cells, B-cells, NK cells, monocytes, DCs, and TILs PD-L1 Melanoma, lung cancer, ovarian cancer, colon cancer, and many other human cancer tissues CTLA-4 Activated T-cells, NK cells, and many other immune cell types LAG-3 Activated CD4 + and CD8 + T-cells, Treg and NK cells, B-cells, and plasma cell-like DCs TIGIT T-cells and NK cells, and usually low expression on naive cells B7-H3 Overexpression in CRC and many other human cancer tissues 2 VISTA Hematopoietic stem cells, myeloid cells, lymphoid and myeloid DCs; Less on CD4 + and CD8 + T-cells and Treg cells, and also detected on TILs HHLA2 Restricted except in epithelial cells of the intestine, kidney, gallbladder, breast, and trophoblast of the placenta 2.1.1　Regulation of PD-L1 at the nucleic acid level 3 2.1.1.1　Epigenetic regulation 4 The hypomethylation of CpG sites leading to PD-L1 upregulation is the most prevalent epigenetic feature within cancer cells ( Table 2 Table 2 ) (al Emran et al., 2019). DNA methyltransferase inhibitors (DNMTis) are thought to stimulate interferon ( IFN ) genes and produce IFN-‍γ to induce PD-L1 expression by increasing the expression of endogenous retroviruses (ERVs) with hypermethylated DNA (al Emran et al., 2019). Drugs such as azacitidine and decitabine were found to enhance the efficacy of anti-PD-L1 antibodies by upregulating PD-L1 expression through DNA hypomethylation in mouse models of non-small cell lung cancer (NSCLC), colorectal cancer (CRC), gastric cancer (GC), and leukemia ( Yang et al., 2014 Yang et al., 2014 ; Zhang et al., 2017 Zhang et al., 2017 ; Franzen et al., 2018 Franzen et al., 2018 ; Huang et al., 2020 Huang et al., 2020 ; Zhu et al., 2020 Zhu et al., 2020 ), providing a more significant antitumor effect than anti-PD-L1 treatment alone ( Zhu et al., 2020 Zhu et al., 2020 ). In addition, tri-methylation of lysine 4 on histone H3 (H3K4me3) was found to be a histone modifier reflecting the transcriptional activation status of the gene ( Howe et al., 2017 Howe et al., 2017 ). Mixed lineage leukemia 1 (MLL1), the binding protein of PD-L1 promoter, could catalyze H3K4me3 and thus promote PD-L1 transcription ( Lu et al., 2017 Lu et al., 2017 ). In contrast, verticillin A attenuated the mediating ability of MLL1, thereby downregulating PD-L1 expression at the transcriptional level ( Lu et al., 2017 Lu et al., 2017 ). Besides, T-cell responses can be inhibited in the GC microenvironment rather than through the membrane by lysine-specific demethylase 1A (LSD1), inducing the accumulation of PD-L1 in exosomes, which may provide a new target for immunotherapy ( Shen et al., 2022 Shen et al., 2022 ). In fact, the LSD1 inhibitor (ORY-1001) combined with an anti-CD47/PD-L1 monoclonal antibody inhibits tumor growth more effectively than a single blocking strategy ( Xu et al., 2021 Xu et al., 2021 ). To be continued PD-L1: programmed cell death-ligand 1; NSCLC: non-small cell lung cancer; HNSCC: head and neck squamous cell carcinoma; CRC: colorectal cancer; GC: gastric cancer; H3K4me3: tri-methylation of lysine 4 on histone H3; IFN: interferon; IL: interleukin; HCC: hepatocellular carcinoma; GBM: glioblastoma multiforme; RCC: renal cell carcinoma; TNF-‍α: tumor necrosis factor-‍α; TGF-‍‍β: transforming growth factor-‍‍β; EGFR: epidermal growth factor receptor; LUAD: lung adenocarcinoma; MAPK: mitogen-activated protein kinase; AP-1: activator protein-1; HIF-1: hypoxia-inducible factor-1; ESCC: esophageal squamous cell carcinoma; ALK: anaplastic lymphoma kinase; ZNF36: zinc finger protein 36; AML: acute myeloid leukemia; GSK3β: glycogen synthase kinase 3β; B3GNT3: β‍-1,3-‍ N -acetylglucosaminyltransferase 3; CMTM: CKLF-like MARVEL transmembrane domain-containing; CSN5: COP9 signalosome 5; CDK4: cytokinin-dependent kinase 4; PI3K: phosphatidylinositol 3 kinase; AKT: protein kinase B; mTOR: mammalian target of rapamycin; STT3: dolichyldiphosphooligosaccharide-protein glycosyltransferase subunit STT3. Regulatory type Regulator PD-L1 Cancer type Inhibitors References Epigenetic Methylation at CpG sites Downregulation Melanoma, NSCLC, HNSCC, CRC, GC, leukemia Azacitidine, decitabine Yang et al., 2014 Yang et al., 2014 ; Goltz et al., 2017 Goltz et al., 2017 ; Marwitz et al., 2017 Marwitz et al., 2017 ; Shin et al., 2017 Shin et al., 2017 ; Zhang et al., 2017 Zhang et al., 2017 ; Franzen et al., 2018 Franzen et al., 2018 ; Micevic et al., 2019 Micevic et al., 2019 ; Huang et al., 2020 Huang et al., 2020 ; Zhu et al., 2020 Zhu et al., 2020 H3K4me3 Upregulation Pancreatic cancer and breast cancer Verticillin A Howe et al., 2017 Howe et al., 2017 ; Lu et al., 2017 Lu et al., 2017 ; Darvin et al., 2019 Darvin et al., 2019 Transcriptional IFN-α Upregulation Melanoma Garcia-Diaz et al., 2017 Garcia-Diaz et al., 2017 IFN-β Upregulation Melanoma Garcia-Diaz et al., 2017 Garcia-Diaz et al., 2017 IFN-γ Upregulation Sarcoma, colon cancer, melanoma, and NSCLC Tofacitinib, ruxolitinib, fedratinib,silvestrol, vertiporfin Yao et al., 2015 Yao et al., 2015 ; Ikeda et al., 2016 Ikeda et al., 2016 ; Bu et al., 2017 Bu et al., 2017 ; Garcia-Diaz et al., 2017 Garcia-Diaz et al., 2017 ; Noguchi et al., 2017 Noguchi et al., 2017 ; Cerezo et al., 2018 Cerezo et al., 2018 ; Chang et al., 2018 Chang et al., 2018 ; Chen et al., 2018 Chen et al., 2018 ; Shao et al., 2019 Shao et al., 2019 IL-6 Upregulation Prostate cancer, HCC, GBM, NSCLC, lung cancer Shen et al., 2017 Shen et al., 2017 ; Shin et al., 2017 Shin et al., 2017 ; Xu et al., 2018 Xu et al., 2018 ; Lamano et al., 2019 Lamano et al., 2019 ; Zhang et al., 2020 Zhang et al., 2020 IL-4 Upregulation RCC, kidney cancer Quandt et al., 2014 Quandt et al., 2014 TNF-α Upregulation Kidney cancer Quandt et al., 2014 Quandt et al., 2014 TGF-β Upregulation NSCLC, lung cancer Ni et al., 2012 Ni et al., 2012 ; David et al., 2017 David et al., 2017 EGFR NSCLC and LUAD Akbay et al., 2013 Akbay et al., 2013 ; Gainor et al., 2016 Gainor et al., 2016 PI3K-AKT-mTOR Upregulation GC, NSCLC, CRC, glioma, melanoma, HNSCC, CRC, and Her2-amplifiedcancer Buparlisib, Worman penicillin, trimethymidine phosphate, rapamycin Jiang et al., 2013 Jiang et al., 2013 ; Mittendorf et al., 2014 Mittendorf et al., 2014 ; Lastwika et al., 2016 Lastwika et al., 2016 ; van Rensburg et al., 2018 van Rensburg et al., 2018 ; Peng et al., 2019 Peng et al., 2019 ; Du et al., 2020 Du et al., 2020 ; Fiedler et al., 2020 Fiedler et al., 2020 MAPK Upregulation Multiple human cancer Selumetinib Stutvoet et al., 2019 Stutvoet et al., 2019 ; Yuan et al., 2020 Yuan et al., 2020 AP-1 Upregulation Hodgkin's lymphoma Green et al., 2012 Green et al., 2012 ; Chen et al., 2013 Chen et al., 2013 HIF-1 Upregulation LUAD, RCC Barsoum et al., 2014 Barsoum et al., 2014 Myc Upregulation Melanoma, NSCLC, ESCC, leukemia, lymphoma, and pancreatic cancer Casey et al., 2016 Casey et al., 2016 ; Atsaves et al., 2017 Atsaves et al., 2017 ; Kim et al., 2017 Kim et al., 2017 ; Wang et al., 2017 Wang et al., 2017 ; Cheng et al., 2019 Cheng et al., 2019 ; Pan et al., 2019 Pan et al., 2019 ; Liang et al., 2020 Liang et al., 2020 ; Wang J et al., 2020 Wang J et al., 2020 ALK Downregulation NSCLC, lymphoma, LUAD Marzec et al., 2008 Marzec et al., 2008 ; Yamamoto et al., 2009 Yamamoto et al., 2009 ; Ota et al., 2015 Ota et al., 2015 ; Koh et al., 2016 Koh et al., 2016 ; Shen et al., 2020 Shen et al., 2020 Met Upregulation NSCLC Demuth et al., 2017 Demuth et al., 2017 ; Albitar et al., 2018 Albitar et al., 2018 ; Ahn et al., 2019 Ahn et al., 2019 ; al Emran et al., 2019 al Emran et al., 2019 ; Peng et al., 2019 Peng et al., 2019 RNA-level ZNF36 Downregulation Adriamycin Coelho et al., 2017 Coelho et al., 2017 MiR-148a-3p Downregulation CRC Ashizawa et al., 2019 Ashizawa et al., 2019 MiR-34a Downregulation AML and lymphoma Wang et al., 2015 Wang et al., 2015 ; Anastasiadou et al., 2019 Anastasiadou et al., 2019 MiR-200 family Downregulation NSCLC and GC Chen et al., 2014 Chen et al., 2014 ; Xie et al., 2017 Xie et al., 2017 MiR-142-5p Downregulation Pancreatic cancer Jia et al., 2017 Jia et al., 2017 MiR-424 Downregulation Ovarian cancer Xu et al., 2016 Xu et al., 2016 MiR-214 Downregulation Lymphoma Sun et al., 2019 Sun et al., 2019 MiR-497-5p Downregulation RCC Qu et al., 2019 Qu et al., 2019 MiR-140 Downregulation NSCLC Xie et al., 2018 Xie et al., 2018 2 Post-translational modification Modificationcite Tyr112 Phosphorylation HCC Chan et al., 2019 Chan et al., 2019 Ser195 Phosphorylation Breast cancer Cha et al., 2018 Cha et al., 2018 ; Dai et al., 2021 Dai et al., 2021 Asn192/200/219 Glycosylation Breast cancer Li et al., 2016 Li et al., 2016 Cys272 Palmitoylation Breast cancer and colon cancer Competitive inhibitor Yang et al., 2019 Yang et al., 2019 ; Yao et al., 2019 Yao et al., 2019 Modificationenzyme GSK3β Phosphorylation Breast cancer Olaparib Li CW et al., 2016 Li CW et al., 2016 ; Jiao et al., 2017 Jiao et al., 2017 ; Li H et al., 2019 Li H et al., 2019 STT3 Glycosylation Cancer stem cell Etoposide Hsu et al., 2018 Hsu et al., 2018 ; Li et al., 2018 Li et al., 2018 ; Ruan et al., 2020 Ruan et al., 2020 B3GNT3 Glycosylation Breast cancer D'Arrigo et al., 2017 CMTM4 Ubiquitination NSCLC and melanoma Mezzadra et al., 2017 Mezzadra et al., 2017 CMTM6 Ubiquitination Melanoma, NSCLC, CRC, thyroid cancer, pancreatic cancer, breast cancer Burr et al., 2017 Burr et al., 2017 ; Mezzadra et al., 2017 Mezzadra et al., 2017 ; Wu et al., 2019 Wu et al., 2019 CSN5 Ubiquitination Breast cancer Lim SO et al., 2016 Lim SO et al., 2016 CDK4/6 Ubiquitination Cervical cancer and breast cancer Zhang et al., 2018 Zhang et al., 2018 2.1.1.2　Transcriptional regulation 2.1.1.2.1　Inflammatory signaling PD-L1, a negative feedback regulator molecule of multiple inflammatory signals, can be induced to be upregulated by multiple inflammatory factors, such as IFN-‍‍α, IFN-‍‍β, IFN-‍γ, interleukin-6 (IL‍-6), IL-4, tumor necrosis factor-‍α (TNF-‍‍α), and transforming growth factor-‍‍‍β (TGF‍-‍‍β) ( Table 2 Table 2 ), among which IFN-‍γ is thought to be the main stimulator promoting PD-L1 expression ( Zerdes et al., 2018 Zerdes et al., 2018 ). IFN-‍γ binds to type II IFN receptors and activates the Janus tyrosine kinase (JAK)‍-signal transducer and activator of transcription 1 (STAT1) signaling pathway ( Yao et al., 2015 Yao et al., 2015 ; Garcia-Diaz et al., 2017 Garcia-Diaz et al., 2017 ), subsequently leading to the upregulation of several transcription factors, especially IFN response factors (IRFs). IFN-‍γ‍-induced PD-L1 upregulation through membrane requires cyclin-dependent kinase 5 (CDK5), which inhibits the expression of PD-L1 transcriptional repressors, namely the IFN regulatory factor 2 (IRF2) and IRF2-binding protein 2 (IRF2BP2), which may lead to increased PD-L1 expression in tumors ( Dorand et al., 2016 Dorand et al., 2016 ). Research has speculated that CDK5 may regulate PD-L1 through protein post-translational modification ( Gao et al., 2021 Gao et al., 2021 ), whereas the role of CDK5 in regulating PD-L1 expression remains to be determined. Tofacitinib, ruxolitinib, and fedratinib (small molecule JAK inhibitors) have been shown to downregulate PD-L1 expression in triple-negative breast cancer (TNBC), NSCLC, nasopharyngeal carcinoma (NPC) cells ( Ikeda et al., 2016 Ikeda et al., 2016 ; Chen et al., 2018 Chen et al., 2018 ), and several cancer models, in which the ability to inhibit STAT1 expression by silvestrol also reduced PD-L1 expression ( Ikeda et al., 2016 Ikeda et al., 2016 ; Bu et al., 2017 Bu et al., 2017 ; Cerezo et al., 2018 Cerezo et al., 2018 ). Besides, vertiporfin blocked IFN-‍γ‍-induced STAT1‍–‍IRF1 interactions, leading to the downregulation of PD-L1 transcription. In addition to IFN-‍γ, the type I IFNs, IFN-‍‍α and IFN-‍β, can stimulate PD-L1 expression, but the regulation of PD-L2 by type I IFNs is more pronounced compared to PD-L1 ( Garcia-Diaz et al., 2017 Garcia-Diaz et al., 2017 ). Apart from IFNs, ILs are also important cytokines that regulate PD-L1 expression. The IL-6-JAK-STAT3 pathway can promote PD-L1 expression and thus lead to the immune escape ability of cancer cells ( Shin et al., 2017 Shin et al., 2017 ). Furthermore, in lung cancer, PD-L1 expression derived by IL-6 is associated with multiple pathways, especially the mitogen-activated extracellular signal-regulated kinase (MEK)‍-extracellular signal-regulated kinase (ERK) signaling pathway ( Shen et al., 2017 Shen et al., 2017 ). IL-4 and TNF-‍α can induce PD-L1 transcription in kidney cancer cells by synergistically activating signaling molecules, such as nuclear factor-‍κB (NF‍-‍‍‍κB), inhibitor of NF-‍‍κB (IκB), and STAT6 ( Quandt et al., 2014 Quandt et al., 2014 ). TGF-‍β can upregulate PD-L1 in DCs in lung cancer ( Ni et al., 2012 Ni et al., 2012 ) and upregulate PD-L1 expression in NSCLC through Smad-binding elements ( David et al., 2017 David et al., 2017 ). However, it has also been proven that TGF-‍β can inhibit PD-L1 expression in monocytes or renal tubular epithelial cells ( Starke et al., 2007 Starke et al., 2007 ; Ou et al., 2012 Ou et al., 2012 ). 2.1.1.2.2 Oncogenic signaling 4 The epidermal growth factor receptor (EGFR) is upstream of various key signaling pathways that regulate PD-L1 activity, including phosphatidylinositol 3 kinase (PI3K)‍-protein kinase B (AKT)‍-mammalian target of rapamycin (mTOR), rat sarcoma (RAS)‍-rapidly accelerated fibrosarcoma (RAF)‍-MEK-ERK, JAK-STAT, and glycogen synthase kinase 3 (GSK3) ( Table 2 Table 2 ). Among them, the PI3K-AKT-mTOR pathway can transcriptionally regulate PD-L1 expression through activator protein-1 (AP-1), STAT3, Yes-associated protein 1 (YAP1)/tafazzin (TAZ), and others. PD-L1 expression can be upregulated by regulatory factors such as AP-1, STAT3, and YAP1/TAZ ( Jiang et al., 2013 Jiang et al., 2013 ; van Rensburg et al., 2018 van Rensburg et al., 2018 ; Peng et al., 2019 Peng et al., 2019 ; Du et al., 2020 Du et al., 2020 ), and inhibitors based on different components of this pathway all have regulatory effects on PD-L1 expression, such as buparlisib and wortmannin (PI3K inhibitors) in head and neck squamous cell carcinoma (HNSCC) or breast cancer (BC) cells ( van Rensburg et al., 2018 van Rensburg et al., 2018 ; Fiedler et al., 2020 Fiedler et al., 2020 ), or trimethymidine phosphate (AKT inhibitor, LY294002) and rapamycin (mTOR inhibitor) in NSCLC cells ( Lastwika et al., 2016 Lastwika et al., 2016 ). RAS-RAF-MEK-ERK signaling through AP1 and STAT3 can also upregulate PD-L1 transcription. The mitogen-activated protein kinase (MAPK) pathway is a broad pathway of carcinogenesis, accounting for nearly 40% of human cancer cases ( Yuan et al., 2020 Yuan et al., 2020 ). The MEK inhibitor selumetinib inhibited the epidermal growth factor (EGF)‍- and IFN-stimulated upregulation of PD-L1 messenger RNA (mRNA) and protein by blocking the MAPK signaling pathway ( Stutvoet et al., 2019 Stutvoet et al., 2019 ). In addition, mutations in hypoxia-inducible factor-1 (HIF-1) ( Barsoum et al., 2014 Barsoum et al., 2014 ), Myc ( Casey et al., 2016 Casey et al., 2016 ; Kim et al., 2017 Kim et al., 2017 ; Pan et al., 2019 Pan et al., 2019 ; Liang et al., 2020 Liang et al., 2020 ), anaplastic lymphoma kinase (ALK) ( Ota et al., 2015 Ota et al., 2015 ), and mesenchymal-epithelial transition factor (Met) ( Demuth et al., 2017 Demuth et al., 2017 ; al Emran et al., 2019) are also oncogenic factors that affect PD-L1 expression. 2.1.1.3　Regulation of RNA levels 4 Zinc finger protein 36 (ZFP36) can downregulate PD-L1 by destabilizing mRNA ( Coelho et al., 2017 Coelho et al., 2017 ), and although ZFP36 has no direct activator, ZFP36 can be phosphorylated and inactivated by a variety of MAPKs in the RAS-MAPK signaling pathway ( Table 2 Table 2 ) ( Coelho et al., 2017 Coelho et al., 2017 ). Besides, the N 6 -methyladenosine (m 6 A) methylation regulator may be crucial for PD-L1 expression ( Guo et al., 2021 Guo et al., 2021 ). PD-L1 mRNA is a direct target of m 6 A modification, and its levels are regulated by AlkB homolog 5 (ALKBH5), an important m 6 A demethylase. The deletion of ALKBH5 enriches the 3' untranslated region (UTR) of PD-L1 mRNA with m 6 A modifications, thereby promoting its degradation in a YTH m 6 A RNA-binding protein 2 (YTHDF2)‍-dependent manner ( Qiu et al., 2021 Qiu et al., 2021 ). In addition, adriamycin can induce ZFP36 expression, and all of these mechanisms may be the means of inhibition of the indirect pathway. Meanwhile, tumor-derived microRNAs (miRNAs) are also important post-transcriptional regulators of PD-L1. For instance, PD-L1 mRNA is a direct target of miR-148a-3p, and lowering miR-148a-3p can elevate PD-L1 mRNA ( Ashizawa et al., 2019 Ashizawa et al., 2019 ). Thus far, many miRNAs have been identified as direct targets of PD-L1 mRNA, such as miR-34a, the miR-200 family, miR-142-5p, miR-424, miR-214, miR-497-5p, and miR-140 ( Table 2 Table 2 ) ( Chen LM et al., 2014 Chen LM et al., 2014 ; Wang et al., 2015 Wang et al., 2015 ; Xu et al., 2016 Xu et al., 2016 ; Jia et al., 2017 Jia et al., 2017 ; Sun C et al., 2018 Sun C et al., 2018 ; Xie et al., 2018 Xie et al., 2018 ; Anastasiadou et al., 2019 Anastasiadou et al., 2019 ; Qu et al., 2019 Qu et al., 2019 ; Sun JR et al., 2019 Sun JR et al., 2019 ; Chen C et al., 2020 Chen C et al., 2020 ). 2.1.2　Post-translational modifications of PD-L1 3 2.1.2.1　Phosphorylation and glycosylation 4 IL-6-activated JAK1 promotes the phosphorylation of PD-L1 (Tyr112), and the phosphorylated PD-L1 in turn recruits STT3A ( N -glycosyltransferase) to catalyze the glycosylation of PD-L1 ( Chan et al., 2019 Chan et al., 2019 ), which can improve the stability of PD-L1 ( Table 2 Table 2 ). Etoposide can reduce PD-L1 N -glycosylation and its expression in mouse models by inhibiting the expression of STT3 ( Hsu et al., 2018 Hsu et al., 2018 ; Ruan et al., 2020 Ruan et al., 2020 ). Meanwhile, it has been reported that the inhibition of other key molecules mediating PD-L1 glycosylation modifications, such as β‍-‍1,‍3- N -acetylglucosaminyltransferase 3 (B3GNT3) ( Li et al., 2018 Li et al., 2018 ), Sigma1 ( Maher et al., 2018 Maher et al., 2018 ) and spliced isoform of FK506-binding protein 51 (FKBP51s) ( D'Arrigo et al., 2017 D'Arrigo et al., 2017 ), can also reduce the expression level of PD-L1 ( Table 2 Table 2 ). However, metformin-activated AMP-activated protein kinase (AMPK) can promote the phosphorylation of PD-L1 (Ser195), leading to aberrant PD-L1 glycosylation, disrupting the translocation of PD-L1 from the endoplasmic reticulum to the Golgi apparatus, and impeding it at the cell membrane, while also promoting the degradation of endoplasmic reticulum-associated PD-L1 ( Cha et al., 2018 Cha et al., 2018 ; Dai et al., 2021 Dai et al., 2021 ). In addition, GSK3β can reduce PD-L1 levels by promoting phosphorylation-dependent proteasomal degradation ( Li CW et al., 2016 Li CW et al., 2016 ; Li H et al., 2019 Li H et al., 2019 ). Several drugs have been used clinically to indirectly modulate GSK3β activity, thereby affecting PD-L1 stability. For example, olaparib (a poly(ADP-ribose) polymerase inhibitor) induced GSK3β inactivation, which increased PD-L1 expression in cancer cells ( Jiao et al., 2017 Jiao et al., 2017 ). Glycosylation of the Asn192/200/219 site inhibits the formation of the GSK3β‍-‍β‍-transducin repeat-containing protein (β‍-TrCP)‍-PD-L1 complex and stabilizes PD-L1; EGF induces GSK3β glycosylation by promoting inactivation to increase PD-L1 expression ( Table 2 Table 2 ) ( Li et al., 2016 Li et al., 2016 ). 2.1.2.2　Ubiquitination 4 Ubiquitination has been commonly associated with proteasome-mediated protein degradation ( Table 2 Table 2 ). In a variety of cancer cells, CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6) prolongs PD-L1 half-life by reducing PD-L1 ubiquitination ( Mezzadra et al., 2017 Mezzadra et al., 2017 ; Wu et al., 2019 Wu et al., 2019 ), while CMTM4 also has the same function ( Mezzadra et al., 2017 Mezzadra et al., 2017 ). Upon the knockdown of CMTM6, the E3 ubiquitin ligase STIP1 homology and U-box-containing protein 1 (STUB1) induces PD-L1 polyubiquitination ( Burr et al., 2017 Burr et al., 2017 ; Mezzadra et al., 2017 Mezzadra et al., 2017 ). In addition, the TNF-‍α‍-‍NF-‍‍κB pathway inhibits PD-L1 ubiquitination by upregulating COP9 signalosome 5 (CSN5) ( Lim SO et al., 2016 Lim SO et al., 2016 ). Meanwhile, cytokinin-dependent kinase 4 (CDK4) indirectly promotes PD-L1 ubiquitination by phosphorylating speckle type BTB/POZ protein (SPOP) (an E3 ubiquitin ligase cullin 3 of PD-L1), which inhibits PD-L1 expression ( Zhang et al., 2018 Zhang et al., 2018 ). On this basis, CDK4/6 inhibitors can block the degradation of PD-L1 by inhibiting CDK4. To this end, several clinical trials evaluated the efficacy of CDK4/6 inhibitors in combination with anti-PD-L1/PD-1 antibodies ( Petroni et al., 2020 Petroni et al., 2020 ; Sun et al., 2021 Sun et al., 2021 ; Wu YQ et al., 2021 Wu YQ et al., 2021 ; Zhu et al., 2021 Zhu et al., 2021 ). 2.1.2.3　Palmitoylation 4 Palmitoylation is a widely studied lipid modification at the Cys272 site that enhances PD-L1 stability by counteracting ubiquitination ( Table 2 Table 2 ) ( Yang et al., 2019 Yang et al., 2019 ; Yao et al., 2019 Yao et al., 2019 ). Since DHHC-type palmitoyltransferase 3 (DHHC3) can catalyze the Cys272 palmitoylation reaction of PD-L1, silencing DHHC3 enhances the antitumor immune responses both in vivo and in vitro ( Yao et al., 2019 Yao et al., 2019 ), while DHHC9 plays the same function in BC. By combining a cell-penetrating peptide with the palmitoylation motif of PD-L1, a competitive inhibitor of PD-L1 palmitoylation was produced, which was subsequently proven to diminish PD-L1 palmitoylation and expression ( Yang et al., 2019 Yang et al., 2019 ; Yao et al., 2019 Yao et al., 2019 ). 2.1.2.4　Acetylation 4 Acetylation can regulate the stability, subcellular localization, and functional activity of proteins ( Table 2 Table 2 ). At present, the function of PD-L1 acetylation is unclear. Interestingly, Lys263 acetylation suppresses PD-L1 nuclear translocation, during which unacetylated PD-L1 is transferred to the nucleus via lattice-protein-mediated endocytosis, and nuclear PD-L1 can bind directly to DNA and regulate a variety of immune response-related expression ( Gao et al., 2020 Gao et al., 2020 ). The use of histone deacetylase 2 (HDAC2) inhibitors to upregulate Lys263 acetylation, or the introduction of the proposed acetylated Lys263Gln mutation into PD-L1, disrupts its interaction with huntingtin-interacting protein 1-related (HIP1R), thereby blocking PD-L1 relocalization in the nucleus, reprograming the expression of immune-response-related genes, and enhancing the antitumor response to PD-1 blockade ( Gao et al., 2020 Gao et al., 2020 ; Hou et al., 2020 Hou et al., 2020 ). 2.2 CTLA-4 2 CTLA-4, also known as CD152, is mainly expressed on activated T-cells and NK cells, and it is also expressed on the surface of many immune cells as a receptor protein ( Table 1 Table 1 ), capable of binding CD80 (B7-1)/CD86 (B7-2) and inhibiting T-cell activation through multiple mechanisms. Because of its high homology with CD28 and its higher affinity for the binding sites of B7 molecules of APCs than CD28 ( Rotte, 2019 Rotte, 2019 ), it can inhibit T-cell function. At the same time, CTLA-4 is also expressed on regulatory T (Treg) cell membranes, and it enhances Treg activity and differentiation to inhibit T-cell activation. In addition, CTLA-4 can directly interfere with DCs, thereby promoting immunosuppression in the TME ( Iñarrairaegui et al., 2018 Iñarrairaegui et al., 2018 ). Interestingly, PD-L1 is also able to bind to CD80 to mediate the suppression of T-cell activation ( Butte et al., 2007 Butte et al., 2007 ), a mechanism that is one of the few direct overlapping functions of PD-1/PD-L1 and CTLA-4 ( Korman et al., 2006 Korman et al., 2006 ). Similar to PD-L1, the intracellular localization of CTLA-4 can specifically regulate the anticancer response ( Rowshanravan et al., 2018 Rowshanravan et al., 2018 ); therefore, an understanding of the regulators of CTLA-4 and their regulatory mechanisms can help identify patients who respond well to anti-CTLA-4 therapy and continuously improve the corresponding anticancer strategies. 2.2.1　Regulation of CTLA-4 at the nucleic acid level 3 2.2.1.1　Epigenetic regulation 4 Currently, those studies are rather focused on CTLA-4 and its related molecules, but little is known about their epigenetic regulation, which is essential for the development of predictive biomarkers of immunotherapy response. It has been reported that the altered expression of HDACs can promote tumorigenesis, and the alteration of the HDAC structural domain of transcription factor 1 (Tcf1) can promote CTLA-4 expression in follicular helper T-cells (TFH) ( Table 3 Table 3 ) ( Li et al., 2021 Li et al., 2021 ). Meanwhile, the methylation modification of DNA on CpG sites can also inhibit CTLA-4 expression ( de Vos et al., 2020 de Vos et al., 2020 ). For instance, in normal tissue, the DNA methylation of CpG sites where the CTLA-4 promoter is located was negatively connected with mRNA expression, whereas in tumor tissue, the connection was either positive or negative, depending on the specific CpG site ( de Vos et al., 2020 de Vos et al., 2020 ). In addition, the methylation of CpG site in the CD28 promoter region was inversely linked not only with CD28 mRNA but also with CTLA-4 mRNA expression ( de Vos et al., 2020 de Vos et al., 2020 ). Therefore, it has been postulated that DNA methylation could serve as a biomarker for predicting PD-1 and CTLA-4 ICB responses ( Table 3 Table 3 ) ( Goltz et al., 2018 Goltz et al., 2018 ). CTLA-4: cytotoxic T-lymphocyte-associated antigen-4; HDACs: histone deacetylases; NFAT: nuclear factor of activated T-cells; IL: interleukin; IFN-‍γ: interferon-‍γ; CD: cluster of differentiation; AP: activator protein; GTPases: guanosine triphosphatases; PLD: phospholipase D; ARF: ADP ribosylation factor. Regulatory type Regulators CTLA-4 References Nucleic acid level Epigenetic Methylation at CpG sites Downregulation de Vos et al., 2020 de Vos et al., 2020 HDACs Upregulation Li et al., 2021 Li et al., 2021 Transcriptional NFAT Downregulation Gibson et al., 2007 Gibson et al., 2007 IL-1α Upregulation Nagaraju et al., 1999 Nagaraju et al., 1999 IFN-γ Upregulation Nagaraju et al., 1999 Nagaraju et al., 1999 IL-2 Upregulation Alegre et al., 1996 Alegre et al., 1996 ; Nagaraju et al., 1999 Nagaraju et al., 1999 CD28 Downregulation Nagaraju et al., 1999 Nagaraju et al., 1999 ; Oyewole-Said et al., 2020 Oyewole-Said et al., 2020 RNA level MiR-487a Downregulation Chang et al., 2017 Chang et al., 2017 ; Wang MM et al., 2020 Wang MM et al., 2020 MiR-9 Downregulation Jebbawi et al., 2014 Jebbawi et al., 2014 Cellular localization AP-1 Upregulation Schneider et al., 1999 Schneider et al., 1999 AP-2 Upregulation Linsley et al., 1996 Linsley et al., 1996 ; Shiratori et al., 1997 Shiratori et al., 1997 GTPases, PLD-1, PLD-2, ARF-1 Upregulation Mead et al., 2005 Mead et al., 2005 Ca 2+ Upregulation Linsley et al., 1996 Linsley et al., 1996 2.2.1.2　Transcriptional regulation 4 Thus far, research on the transcriptional regulation of CTLA-4 has been relatively limited. The nuclear factor of activated T-cells (NFAT) binds to the CTLA-4 promoter to elevate CTLA-4 transcription, and mutations in the NFAT locus disrupt the activity of the CTLA-4 promoter; hence the treatment of inhibitors of NFAT leads to the downregulation of CTLA-4 transcription ( Gibson et al., 2007 Gibson et al., 2007 ). In addition, NFAT can interact with Forkhead box P3 (Foxp3) and bind to another promoter of CTLA-4 to activate its transcription ( Wu et al., 2006 Wu et al., 2006 ). Meanwhile, IL-‍1α, IFN-‍γ, IL-2, and the inhibition of CD28 have all been shown to promote CTLA-4 expression ( Table 3 Table 3 ) ( Nagaraju et al., 1999 Nagaraju et al., 1999 ). However, IL-4, IL-6, IL-7, and IL-12 showed only limited induction ( Alegre et al., 1996 Alegre et al., 1996 ). 2.2.1.3　Regulation of RNA levels 4 MiRNAs are important vectors for regulating CTLA-4 expression ( Table 3 Table 3 ). To date, several different miRNAs have been shown to directly regulate the expression of CTLA-4. For example, miR-105 directly binds to the 3' UTR of the mutated allele of CTLA-4 instead of binding to the wild-type allele to regulate its expression. MiR-487a acted as a tumor suppressor in prostate cancer but an oncogenic factor in other cancer types ( Chang et al., 2017 Chang et al., 2017 ; Wang MM et al., 2020 Wang MM et al., 2020 ), where miR-487a-3p can directly target CTLA-4 and reduce its expression. MiR-9 was also found to directly target CTLA-4, and the downregulated expression of this miRNA in Treg cells may correlate with the upregulation of CTLA-4 therein ( Jebbawi et al., 2014 Jebbawi et al., 2014 ). 2.2.2　Cellular localization of CTLA-4 3 The localization analysis of CTLA-4 provides important information because CTLA-4 is mainly localized in the cytoplasm rather than the cell surface. AP-1 binds to the GVYVKM motif of CTLA-4 to maintain a stable intracellular expression level of CTLA-4 ( Schneider et al., 1999 Schneider et al., 1999 ). Similarly, once AP-2 binds to the YVKM or FVKM motif of CTLA-4, CTLA-4 accumulates rather inside the cell than on the surface ( Linsley et al., 1996 Linsley et al., 1996 ; Shiratori et al., 1997 Shiratori et al., 1997 ). Reports have shown that CTLA-4 T-cell surface localization requires the involvement of activated guanosine triphosphatases (GTPases), phospholipase D-1 (PLD-1), PLD-2, and ADP ribosylation factor-1 (ARF-1) ( Mead et al., 2005 Mead et al., 2005 ). Similarly, the rapid upregulation of calcium ions (Ca 2+ ) elevates CTLA-4 expression on the cell surface ( Table 3 Table 3 ) ( Linsley et al., 1996 Linsley et al., 1996 ). 2.2.3　CTLA-4-related antitumor drug development 3 Ipilimumab and tremelimumab were approved by the United States Food and Drug Administration (FDA) in 2011 and 2015 for the treatment of advanced melanoma and malignant mesothelioma, respectively. Ipilimumab upregulates the antitumor activity of T-cells by binding to the MYPPPY motif of CTLA-4 and blocking its interaction with CD80/CD86; meanwhile, tremelimumab binds to CTLA-4 and blocks its binding to the B7 ligand, thereby inhibiting the decrease in T-cell activity mediated by B7-CTLA-4. Currently, there are still significant limitations in the monotherapy of ipilimumab and tremelimumab, although combination therapy regimens related to them are under investigation. Ipilimumab has been approved as a combination with nivolumab (PD-1 inhibitor) for the treatment of unresectable (advanced) melanoma, renal cell carcinoma (RCC), and MSI-h (metastatic microsatellite instability high), or mismatched (repair-deficient) CRC ( Klein et al., 2021 Klein et al., 2021 ). In addition, a synthetic peptide p344 was shown to bind to the MYPPPY motif of CTLA-4 and block its interaction with the B7 ligand ( Podlesnykh et al., 2021 Podlesnykh et al., 2021 ). 3 Roles of novel IC molecules in immune escape 1 3.1 LAG-3 2 Lymphocyte activation gene-3 (LAG-3), also known as CD223, is mainly expressed on activated CD4 + and CD8 + T-cells, Treg and NK cells, as well as B cells and plasma cell-like DCs ( Table 1 Table 1 ). LAG-3 has a similar molecular structure to CD4 and binds more strongly to major histocompatibility complex-II (MHC-II). Upon binding, it transmits negative regulatory signals through the TCR-CD3 complex, thereby inhibiting T-cell proliferation and cytokine production. It also binds other ligands including galectin-3, liver sinusoidal endothelial cell lectin (LSECtin), α‍-synuclein, and fibrinogen-like protein 1 (FGL1), thus inducing immune cell depletion and reducing cytokine secretion ( Baixeras et al., 1992 Baixeras et al., 1992 ; Huard et al., 1994 Huard et al., 1994 ; Kouo et al., 2015 Kouo et al., 2015 ; Anderson et al., 2016 Anderson et al., 2016 ; Baumeister et al., 2016 Baumeister et al., 2016 ; Mao et al., 2016 Mao et al., 2016 ; Wang J et al., 2019 Wang J et al., 2019 ). To date, more than 20 drug designs and clinical trials targeting LAG-3 have been established. IMP321 is the first LAG-3Ig fusion protein developed as a vaccine immune adjuvant, which binds to MHC-II molecules on naive DCs to promote their maturation and thus antigen presentation to tumor cells while upregulating co-stimulatory molecules and increasing IL-12 production to enhance antitumor immune responses. LAG525 is a human anti-LAG-3 monoclonal antibody that interferes with the binding of MCH-II molecules to LAG-3 ( Nguyen and Ohashi, 2015 Nguyen and Ohashi, 2015 ). Other LAG-3 inhibitory antibodies are under experimental evaluation, such as AVA-017 (LAG-3 antagonist), MK-4280, REGN3767, Sym022, and relatlimab. 3.2 TIGIT 2 T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), also known as Washington University Cell Adhesion Molecule (WUCAM), is mainly expressed on T-cells and NK cells, and usually has a low expression on naive cells ( Table 1 Table 1 ). However, some studies have demonstrated that TIGIT appears to be upregulated on both activated T-cells and NK cells ( Harjunpää and Guillerey, 2020 Harjunpää and Guillerey, 2020 ). The TIGIT ligands are mainly CD155, CD112, and CD133, with CD155 having a higher affinity, which is highly expressed on the tumor surface. Once TIGIT binds to CD155, the antitumor effects will be inhibited, which include the inhibition of NK cell-mediated tumor killing, the induction of immunosuppression, the inhibition of CD8 T-cell initiation and differentiation, and the blocking of CD8 T-cell-mediated killing ( Buisson and Triebel, 2005 Buisson and Triebel, 2005 ; Li et al., 2014 Li et al., 2014 ; Fuhrman et al., 2015 Fuhrman et al., 2015 ; Kurtulus et al., 2015 Kurtulus et al., 2015 ; Liu et al., 2015 Liu et al., 2015 ; Kourepini et al., 2016 Kourepini et al., 2016 ). Currently, various TIGIT monoclonal antibodies are being evaluated in clinical trials as therapeutic agents for refractory solid tumors, either as single drugs or in combination with other agents, such as BMS-986207, domvanalimab (AB-154), ASP-8374, and COM902. 3.3 B7 family (B7-H3, B7-H4, VISTA, and HHLA2) 2 At present, there are at least ten members of the B7 family species, of which the B7 homolog 3 protein (B7-H3, CD276), immunoglobulin V structural domain-containing T-cell activation suppressor (VISTA, B7-H5), and human endogenous retroviral H long terminal repeat-binding protein 2 (HHLA2, B7-H7) are the highest mRNA-expressing checkpoint molecules in CRC ( Wang CG et al., 2020 Wang CG et al., 2020 ). Meanwhile, the B7-H4 is also abnormally expressed in tumors, inflammation and autoimmune diseases ( Greenwald et al., 2005 Greenwald et al., 2005 ; Ceeraz et al., 2013 Ceeraz et al., 2013 ). In most normal tissues, B7-H3 commonly exhibits relatively low protein expression ( Sun et al., 2002 Sun et al., 2002 ; Flem-Karlsen et al., 2020 Flem-Karlsen et al., 2020 ). B7-H3 is overexpressed in most human cancers ( Table 1 Table 1 ), which correlates with poor patient prognosis ( Castellanos et al., 2017 Castellanos et al., 2017 ). In T-cell regulation, B7-H3 is considered to be a conflicting co-repressor and co-stimulatory molecule, selectively enhancing IFN-‍γ production and promoting cellular immunity in the presence of TCR signaling ( Chapoval et al., 2001 Chapoval et al., 2001 ; Zhang et al., 2004 Zhang et al., 2004 ); however, a growing body of evidence suggests that B7-H3 plays a negative regulatory role in antitumor immunity ( Chapoval et al., 2001 Chapoval et al., 2001 ; Suh et al., 2003 Suh et al., 2003 ; Zhang et al., 2004 Zhang et al., 2004 ; Mahnke et al., 2007 Mahnke et al., 2007 ; Leitner et al., 2009 Leitner et al., 2009 ; Lee et al., 2017 Lee et al., 2017 ). B7-H4 mRNA can be detected in most non-hematopoietic tissues, while protein expression is more limited and confined to the induced expression on APCs as well as cancer cells. It has been associated with poor clinical and pathological features ( Emaldi and Nunes-Xavier, 2022 Emaldi and Nunes-Xavier, 2022 ) and identified as a novel marker or therapeutic target for the treatment of tumors ( Wang and Wang, 2020 Wang and Wang, 2020 ) by studies assessing the level of soluble B7-H4 in the serum ( Shi et al., 2014 Shi et al., 2014 ; Radichev et al., 2016 Radichev et al., 2016 ). Mounting evidence suggests that B7-H4 negatively regulates T-cell immune response by inhibiting T-cell proliferation, cytokine secretion, and the cell cycle, thereby promoting immune escape ( Sica et al., 2003 Sica et al., 2003 ; Ou et al., 2006 Ou et al., 2006 ; Luan et al., 2009 Luan et al., 2009 ; Xu et al., 2014 Xu et al., 2014 ; Paiva et al., 2016 Paiva et al., 2016 ). VISTA is a negative immunomodulatory factor identified in recent years and expressed mainly on hematopoietic stem cells, with its highest expression level on myeloid cells, lymphoid and myeloid DCs, and lower levels on CD4 + and CD8 + T-cells and Treg cells ( Table 1 Table 1 ) ( Liu et al., 2015 Liu et al., 2015 ). VISTA is also expressed on TILs ( Wang JH et al., 2019 Wang JH et al., 2019 ), acting as a suppressor of CD4 + and CD8 + T-cells and directly inhibiting T-cell activation both in vitro and in vivo ( Ni and Dong, 2017 Ni and Dong, 2017 ). VISTA has also been discovered to reduce Toll-like receptor (TLR)‍-mediated activation of MAPK/AP-1 and inhibitor of NF-‍κB kinase (IKK)/NF-‍‍‍κB signaling cascades, which controls myeloid cell-mediated inflammation and immunosuppression. HHLA2 is a newly discovered member of the B7 family, and its mRNA is widely expressed in human tissues ( Wang B et al., 2019 Wang B et al., 2019 ); however, it has very limited protein levels except in epithelial cells of the intestine, kidney, gallbladder, breast, and trophoblast of the placenta ( Table 1 Table 1 ) ( Janakiram et al., 2015 Janakiram et al., 2015 ). HHLA2 may control intestinal inflammation, and this phenomenon is usually considered to occur through the expression of HHLA2 in the intestine ( Janakiram et al., 2015 Janakiram et al., 2015 ). Moreover, HHLA2 has been reported to bind to CD28H on T-cells and promote T-cell proliferation and cytokine production through an AKT-dependent signaling cascade ( Zhu et al., 2013 Zhu et al., 2013 ). 3.4 Co-immunotherapy against novel ICs 2 It was found that the blockade of LAG-3 alone did not restore T-cell depletion, but the combination of LAG-3 with PD-L1 was able to achieve a significant reduction in tumor size ( Woo et al., 2012 Woo et al., 2012 ). For example, eftilagimod α (LAG-3-Fc fusion protein) and pembrolizumab (anti-PD-1 monoclonal antibody) could be combined for NSCLC and HNSCC ( Peguero et al., 2019 Peguero et al., 2019 ). To this end, BI754111 (anti-LAG-3 monoclonal antibody) and BI754091 (anti-PD-1 monoclonal antibody) were combined for the treatment of refractory solid tumors. Several studies have shown that TIGIT and PD-1 are co-expressed and interrelated ( Johnston et al., 2014 Johnston et al., 2014 ; Chauvin et al., 2015 Chauvin et al., 2015 ), suggesting the presence of potential mechanisms to amplify the immune response to enhance antitumor activity, which provides the theoretical foundation for the combination of TIGIT and PD-1 as blockade therapy. In January 2021, tiragolumab, a novel cancer immunotherapy agent targeting the combination of TIGIT, was designated by FDA as breakthrough therapy for the proposed use as a combination with atezolizumab (a PD-L1 antibody) for the treatment of patients with metastatic NSCLC with high PD-L1 expression and no EGFR or ALK genomic tumor aberrations. In addition, various other anti-TIGIT antibodies are in the process of development and clinical trials, such as vibostolimab (MK-7684) in combination with pembrolizumab (PD-L1 antibody) for melanoma, and ociperlimab (BGB-A1217) in combination with an anti-PD-1 antibody. B7-H3 is a potential target molecule for targeted therapeutic agents because of its wide overexpression on cancer cells and tumor-infiltrating vessels in many tumor types, while it is undetectable in normal tissues. For example, enoblituzumab (MGA271), an anti-B7-H3 monoclonal antibody with antibody-dependent cytotoxicity (ADCC), has been investigated in a variety of solid tumors, including pediatric tumors. It is currently used as a monotherapy agent, or in combination with anti-PD-1 antibodies (revansumab or pembrolizumab) or anti-CTLA-4 antibodies (ipilimumab). It has been reported that B7-H4, an actionable IC protein, plays a role in current treatment-resistant cases of advanced kidney cancer in combination with targeted therapy ( Emaldi and Nunes-Xavier, 2022 Emaldi and Nunes-Xavier, 2022 ). However, most of the antibodies used to identify B7-H4 protein expression are not commercially available ( Podojil and Miller, 2017 Podojil and Miller, 2017 ). With the exception of classical monoclonal antibodies such as 1D11 ( Leong et al., 2015 Leong et al., 2015 ), recombinant single-chain variable fragments (scFvs) against B7-H4 have been reported, which completely reverse the B7-H4-induced inhibition of T-cell function ( Dangaj et al., 2013 Dangaj et al., 2013 ). Notably, VISTA (PD-1H), a homolog of PD-1, has a similar structural domain to PD-1, except that it lacks the classical ITIM or the immunoreceptor tyrosine transition motif (ITSM) in the cytoplasmic structural domain ( Flies et al., 2011 Flies et al., 2011 ). Currently, there are few anti-VISTA antibodies in clinical trials, even though their similar but non-overlapping properties make them ideal therapeutic agents to overcome immunosuppression. HHLA2 is widely expressed in PD-1-negative NSCLC patients, suggesting that it may be a promising therapeutic target when PD-1 pathway blockade is ineffective in some patients ( Cheng et al., 2018 Cheng et al., 2018 ). To date, there have been few studies on HHLA2, which may be related to its underexpression in experimental mice. HHLA2 is highly expressed at the mRNA and protein levels in certain cells, making it a potential immunotherapeutic target for CRC patients. 4 Perspectives 1 Thus far, the clinical values of drugs such as inhibitors and antibodies to PD-1/PD-L1 and CTLA-4 have been demonstrated in many cancer patients, and novel ICs such as LAG-3, TIGIT, B7-H3, and their combination therapies have greatly enriched the options of cancer immunotherapy. Meanwhile, for a large proportion of patients, the currently known ICIs do not seem to work. Thus, more details of the mechanisms and strategies of immunomodulation, cancer, and cancer patients need to be understood. In addition, ICIs face numerous problems and challenges, including immune-related side effects, the development of ICI resistance, and the lack of effective biomarkers. In response, many studies have been published on the expression of IC molecules in TME, and accumulating evidence demonstrates that different oncogenic signaling pathways are involved at the transcriptional, post-transcriptional, and post-translational levels, that is, multiple potential mechanisms lead to the abnormal expression of IC molecules, such as PD-L1 and CTLA-4, in various malignancies. These expression abnormalities are often associated with the immune escape of cancer cells. Therefore, it is important to study the regulation of IC molecule expression during the development of immunotherapies for cancer. In the immune evasion of tumor cells, these regulatory mechanisms and molecules form a complex network, controlling immunological checkpoint molecules at multiple levels. Nonetheless, a number of questions remain unanswered. Firstly, although the tasks performed by these regulatory molecules and processes at their respective nodes have been clarified, the correlations among them, such as the presence of compensatory or synergistic mechanisms between distinct pathways, have not yet been clarified. Clarifying the relationships between these regulatory elements will have significant theoretical implications for the development of combination immunotherapy targets and medicines. Secondly, as a continuation of the preceding topic, the composition of the TME differs significantly between cancer types and even between patients, which in part influences the heterogeneity of tumor immune escape regulatory mechanisms and IC regulation mechanisms. With the development of cutting-edge technologies such as single-cell sequencing, the identification of major IC molecules that mediate immune evasion in various cancer species, as well as the identification of new IC molecules, is expected to emerge as a vital area of immunotherapy research. In the meantime, the pursuit to identify the primary regulators of IC regulation under varying conditions has major clinical implications and may yield novel ideas for combating immunotherapy resistance. Finally, research on the regulation mechanisms of opposing immunological checkpoints has led to the development of a number of small-molecule and antibody-based therapies. The majority of them have demonstrated promising outcomes in animal research; nevertheless, their performance in clinical therapies, particularly their potential toxicity, remains to be evaluated ( Huang et al., 2021 Huang et al., 2021 ). Due to the complexity and interconnectedness of the human immune system, even a minor effect might have undesired effects. Despite the current challenges, we anticipate that as research on ICs continues, we will eventually obtain a deeper and more systematic understanding of tumor immune escape and immunological checkpoints. More specific and improved regulatory systems will be elucidated, and the continued development of new medications and cures will take place. From the past to the future, all discoveries of spectacular regulating mechanisms of immunological checkpoints will be of considerable importance. References Agata Y , Kawasaki A , Nishimura H , et al. , 1996 . 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Int Immunopharmacol , 82 : 106245 . https://doi.org/10.1016/j.intimp.2020.106245 https://doi.org/10.1016/j.intimp.2020.106245 Epigenetically silenced PD-L1 confers drug resistance to anti-PD1 therapy in gastric cardia adenocarcinoma Zhu YW , Yao S , Iliopoulou BP , et al. , 2013 . B7-H5 costimulates human T cells via CD28H . Nat Commun , 4 : 2043 . https://doi.org/10.1038/ncomms3043 https://doi.org/10.1038/ncomms3043 B7-H5 costimulates human T cells via CD28H Aifu LIN determined the topic of the article and proposed this program. Zerui GAO, Xingyi LING, Chengyu SHI, and Ying WANG collected the literature. Zerui GAO and Xingyi LING summarized and drew a diagram of the mechanism. Zerui GAO, Xingyi LING, Chengyu SHI, and Aifu LIN wrote the manuscript. All authors have read and approved the final manuscript. This work was supported by the National Key Research and Development Program of China (No. 2021YFC2700903), the National Natural Science Foundation of China (Nos. 81672791 and 81872300), the Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China (No. LR18C060002), the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (No. LHDMY22H160006), and the ZJU-QILU Joint Research Institute and Qilu Group. 10.1631/jzus.B2200195 1673-1581（2022）10-0823-21 This work was supported by the National Key Research and Development Program of China (No. 2021YFC2700903), the National Natural Science Foundation of China (Nos. 81672791 and 81872300), the Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China (No. LR18C060002), the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (No. LHDMY22H160006), and the ZJU-QILU Joint Research Institute and Qilu Group. 2022-04-04 2022-07-13 2022-10-15 2022-12-27 2022-08-26 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2022 浙江大学出版社 Zerui GAO, Xingyi LING, Chengyu SHI, Ying WANG, and Aifu LIN declare that they have no conflict of interest. This review does not contain any studies with human or animal subjects performed by any of the authors. Compliance with ethics guidelines 浙江大学学报（英文版）（B辑：生物医学和生物技术） 10 23