Unravelling T cell exhaustion through co-inhibitory receptors and its transformative role in cancer immunotherapy

Abstract

Persistent stimulation from cancer antigens leads to T lymphocytes (T cells) exhaustion, with up-regulated expression of co-inhibitory receptors, including programmed death-1 (PD-1), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin domain 3 (TIM-3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These receptors collectively impair T cell function via distinct molecular pathways, contributing to immune evasion and cancer progression. This review highlights the therapeutic promise of immune checkpoint inhibitors (ICIs) in reversing T cell exhaustion while delving into the complex molecular processes and functional works of these important co-inhibitory receptors in tumourigenesis. Additionally, we examine the synergistic effects of combining ICIs with other therapeutic strategies, which can enhance anti-tumour efficacy. Finally, the clinical implications of bispecific antibodies are highlighted, representing a promising frontier in cancer immunotherapy, that could revolutionise treatment paradigms while improving patient outcomes.

Keywords

co-inhibitory receptors / exhaustion / immune checkpoint inhibitors / immunotherapy / T cell / tumour immunity

References

[1] Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331: 1565-1570.

[2] Miller JFAP, Sadelain M. The journey from discoveries in fundamental immunology to cancer immunotherapy. Cancer Cell. 2015; 27: 439-449.

[3] Sun LA, Su YH, Jiao AJ, Wang X, Zhang BJ. T cells in health and disease. Signal Transduct Tar. 2023; 8: 235.

[4] Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature Reviews Immunology. 2013; 13: 227-242.

[5] Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999; 401: 708-712.

[6] Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature Immunology. 2003; 4: 1191-1198.

[7] Belk JA, Daniel B, Satpathy AT. Epigenetic regulation of T cell exhaustion. Nature Immunology. 2022; 23: 848-860.

[8] Franco F, Jaccard A, Romero P, Yu YR, Ho PC. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab. 2020; 2: 1001-1012.

[9] Wherry EJ. T cell exhaustion. Nature Immunology. 2011; 12: 492-499.

[10] Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nature Reviews Immunology. 2015; 15: 486-499.

[11] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12: 252-264.

[12] Beltra J-C, Manne S, Abdel-Hakeem MS, et al. Developmental relationships of four exhausted CD8⁺T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity. 2020; 52: 825-+.

[13] Wing K, Onishi Y, Prieto-Martin P, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008; 322: 271-275.

[14] Qureshi OS, Zheng Y, Nakamura K, et al. Trans-Endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science. 2011; 332: 600-603.

[15] Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012; 209: 1201-1217.

[16] Quigley M, Pereyra F, Nilsson B, et al. Transcriptional analysis of HIV-specific CD8 T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nature Medicine. 2010; 16: 1147-U1127.

[17] Latchman Y, Wood CR, Chernova T, et al. PD-L2, a novel B7 homologue, is a second ligand for PD-1 and inhibits T cell activation. Faseb J. 2001; 15: A345-A345.

[18] Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nature Medicine. 2002; 8: 793-800.

[19] Curiel TJ, Wei S, Dong H, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nature Medicine. 2003; 9: 562-567.

[20] Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annual Review of Immunology. 2008; 26: 677-704.

[21] Lázár-Molnár E, Yan Q, Cao E, Ramagopal U, Nathenson SG, Almo SC. Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. P Natl Acad Sci USA. 2008; 105: 10483-10488.

[22] Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. New Engl J Med. 2012; 366: 2455-2465.

[23] Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. New Engl J Med. 2015; 372: 2018-2028.

[24] Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. New Engl J Med. 2015; 372: 311-319.

[25] Tseng S-Y, Otsuji M, Gorski K, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med. 2001; 193: 839-845.

[26] Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T. Structure and chromosomal localization of the human Pd-1 gene (Pdcd1). Genomics. 1994; 23: 704-706.

[27] Hui E, Cheung J, Zhu J, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017; 355: 1428-+.

[28] Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009; 229: 114-125.

[29] Sheppard K-A, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. Febs Lett. 2004; 574: 37-41.

[30] Staron MM, Gray SM, Marshall HD, et al. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8 T cells during chronic infection. Immunity. 2014; 41: 802-814.

[31] Chamoto K, Chowdhury PS, Kumar A, et al. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. P Natl Acad Sci USA. 2017; 114: E761-E770.

[32] Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal. 2012; 5: ra46.

[33] Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nature Reviews Immunology. 2018; 18: 153-167.

[34] Banta KL, Xu X, Chitre AS, et al. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8 T cell responses. Immunity. 2022; 55: 512-+.

[35] Celis-Gutierrez J, Blattmann P, Zhai Y, et al. Quantitative interactomics in primary T cells provides a rationale for concomitant PD-1 and BTLA coinhibitor blockade in cancer immunotherapy. Cell Rep. 2019; 27: 3315-+.

[36] Rota G, Niogret C, Dang AT, et al. Shp-2 is dispensable for establishing T cell exhaustion and for PD-1 signaling. Cell Rep. 2018; 23: 39-49.

[37] Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8: 793-800.

[38] Garcia-Diaz A, Shin DS, Moreno BH, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep. 2019; 29: 3766.

[39] Komura N, Mabuchi S, Shimura K, et al. The role of myeloid-derived suppressor cells in increasing cancer stem-like cells and promoting PD-L1 expression in epithelial ovarian cancer. Cancer Immunol Immunother. 2020; 69: 2477-2499.

[40] Liu X, Zhang Y, Han Y, et al. Overexpression of GLT1D1 induces immunosuppression through glycosylation of PD-L1 and predicts poor prognosis in B-cell lymphoma. Mol Oncol. 2020; 14: 1028-1044.

[41] Zhang J, Bu X, Wang H, et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature. 2018; 553: 91-95.

[42] Burr ML, Sparbier CE, Chan Y-C, et al. CMTM6 maintains the expression of PD-L1 and regulates anti-tumour immunity. Nature. 2017; 549: 101-105.

[43] Diskin B, Adam S, Cassini MF, et al. PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer. Nat Immunol. 2020; 21: 442-454.

[44] Sun S, et al. CE: Please provide all authors instead fo et al. Ui cound not find it on data internet. PD-1+immune cell infiltration inversely correlates with survival of patients with operable breast cancer. Eur J Cancer. 2013; 49: S211-S211.

[45] Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al. Tumor-infiltrating NY-ESO-1-specific CD8 T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. P Natl Acad Sci USA. 2010; 107: 7875-7880.

[46] Seo AN, Kang BW, Kwon OK, et al. Intratumoural PD-L1 expression is associated with worse survival of patients with Epstein-Barr virus-associated gastric cancer. Br J Cancer. 2017; 117: 1753-1760.

[47] Wang S, Li J, Xie J, et al. Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin beta4/SNAI1/SIRT3 signaling pathway. Oncogene. 2018; 37: 4164-4180.

[48] Wang W, Wang K, Chen Z, et al. Immunoclassification characterized by CD8 and PD-L1 expression is associated with the clinical outcome of gastric cancer patients. Oncotarget. 2018; 9: 12164-12173.

[49] Kawazoe A, Shitara K, Kuboki Y, et al. Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer. Gastric Cancer. 2019; 22: 69-76.

[50] Satpathy AT, Granja JM, Yost KE, et al. Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat Biotechnol. 2019; 37: 925-+.

[51] Khan O, Giles JR, McDonald S, et al. TOX transcriptionally and epigenetically programs CD8 T cell exhaustion. Nature. 2019; 571: 211-+.

[52] Tsui C, Kretschmer L, Rapelius S, et al. MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature. 2022; 609: 354-360.

[53] Tang DL, Kang R, Zeh HJ, Lotze MT. The multifunctional protein HMGB1: 50 years of discovery. Nature Reviews Immunology. 2023; 23: 824-841.

[54] Chen J, López-Moyado IF, Seo H, et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature. 2019; 567: 530-534.

[55] Zhang J, Li J, Hou Y, et al. Osr2 functions as a biomechanical checkpoint to aggravate CD8++ T cell exhaustion in tumor. Cell. 2024; 187.

[56] Fagerberg E, Attanasio J, Dien C, et al. KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection. Science. 2025; 387: eadn2337.

[57] Watson MJ, Vignali PDA, Mullett SJ, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021; 591: 645-+.

[58] Kumagai S, Togashi Y, Kamada T, et al. The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nature Immunology. 2020; 21: 1346-+.

[59] Chan DV, Gibson HM, Aufiero BM, et al. Differential CTLA-4 expression in human CD4 versus CD8 T cells is associated with increased NFAT1 and inhibition of CD4 proliferation. Genes Immun. 2014; 15: 25-32.

[60] Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. 2018; 8: 86.

[61] Leung HT, Bradshaw J, Cleaveland JS, Linsley PS. Cytotoxic T-lymphocyte-associated molecule-4, a high avidity receptor for Cd80 and Cd86, contains an intracellular-localization motif in its cytoplasmic tail. J Biol Chem. 1995; 270: 25107-25114.

[62] Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009; 229: 12-26.

[63] Salvi S, Fontana V, Boccardo S, et al. Evaluation of CTLA-4 expression and relevance as a novel prognostic factor in patients with non-small cell lung cancer. Cancer Immunol Immun. 2012; 61: 1463-1472.

[64] Huang P-Y, Guo S-S, Zhang Y, et al. Tumor CTLA-4 overexpression predicts poor survival in patients with nasopharyngeal carcinoma. Oncotarget. 2016; 7: 13060-13068.

[65] Triebel F, Jitsukawa S, Baixeras E, et al. Lag-3, a novel lymphocyte-activation gene closely related to Cd4. J Exp Med. 1990; 171: 1393-1405.

[66] Li NY, Workman CJ, Martin SM, Vignali DAA. Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223). J Immunol. 2004; 173: 6806-6812.

[67] Li N, Wang Y, Forbes K, et al. Metalloproteases regulate T-cell proliferation and effector function via LAG-3. Embo J. 2007; 26: 494-504.

[68] Andrews LP, Somasundaram A, Moskovitz JM, et al. Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding. Sci Immunol. 2020; 5: eabc2728.

[69] Huard B, Mastrangeli R, Prigent P, et al. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. P Natl Acad Sci USA. 1997; 94: 5744-5749.

[70] Workman CJ, Dugger KJ, Vignali DAA. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J Immunol. 2002; 169: 5392-5395.

[71] Maruhashi T, Okazaki I-M, Sugiura D, et al. LAG-3 inhibits the activation of CD4 T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nature Immunology. 2018; 19: 1415-+.

[72] Jiang Y, Dai A, Huang Y, et al. Ligand-induced ubiquitination unleashes LAG3 immune checkpoint function by hindering membrane sequestration of signaling motifs. Cell. 2025; 188(9): 2354-2371.e18.

[73] Maeda TK, Sugiura D, Okazaki IM, Maruhashi T, Okazaki T. Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation. J Biol Chem. 2019; 294: 6017-6026.

[74] Mastrangeli R, Micangeli E, Donini S. Cloning of murine LAG-3 by magnetic bead bound homologous probes and PCR (GENE-CAPTURE PCR). Anal Biochem. 1996; 241: 93-102.

[75] Ruffo E, Wu RC, Bruno TC, Workman CJ, Vignali DAA. Lymphocyte-activation gene 3 (LAG3): the next immune checkpoint receptor. Semin Immunol. 2019; 42: 101305.

[76] Iouzalen N, Andreae S, Hannier S, Triebel F. LAP, a lymphocyte activation gene-3 (LAG-3)-associated protein that binds to a repeated EP motif in the intracellular region of LAG-3, may participate in the down-regulation of the CD3/TCR activation pathway. Eur J Immunol. 2001; 31: 2885-2891.

[77] Baixeras E, Huard B, Miossec C, et al. Characterization of the lymphocyte-activation gene 3-encoded protein—a new ligand for human-leukocyte antigen class-ii antigens. J Exp Med. 1992; 176: 327-337.

[78] Kouo T, Huang L, Pucsek AB, et al. Galectin-3 shapes antitumor immune responses by suppressing CD8 T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res. 2015; 3: 412-U128.

[79] Xu F, Liu J, Liu D, et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res. 2014; 74: 3418-3428.

[80] Wang J, Sanmamed MF, Datar I, et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell. 2019; 176: 334-+.

[81] Mao X, Ou MT, Karuppagounder SS, et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science. 2016; 353: aah3374.

[82] Saka D, Gökalp M, Piyade B, et al. Mechanisms of T-cell exhaustion in pancreatic cancer. Cancers. 2020; 12: 2274.

[83] Saleh RR, Peinado P, Fuentes-Antrás J, et al. Prognostic value of lymphocyte-activation gene 3 (LAG3) in cancer: a meta-analysis. Front Oncol. 2019; 9: 1040.

[84] Andrews LP, Butler SC, Cui J, et al. LAG-3 and PD-1 synergize on CD8+T cells to drive T cell exhaustion and hinder autocrine IFN-y-dependent anti-tumor immunity. Cell. 2024; 187.

[85] Cillo AR, Cardello C, Shan F, et al. Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+T cells to promote antitumor immunity. Cell. 2024; 187.

[86] Ngiow SF, Manne S, Huang YJ, et al. LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 Tcell NK receptor expression and cytotoxicity. Cell. 2024; 187: 4336-4354.e4319.

[87] Gandhi AK, Kim WM, Sun Z-YJ, et al. High resolution X-ray and NMR structural study of human T-cell immunoglobulin and mucin domain containing protein-3. Sci Rep-Uk. 2018; 8: 17512.

[88] Lee J, Su EW, Zhu C, et al. Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways. Mol Cell Biol. 2011; 31: 3963-3974.

[89] Rangachari M, Zhu C, Sakuishi K, et al. Bat3 promotes T cell responses and autoimmunity by repressing Tim-3-mediated cell death and exhaustion. Nature Medicine. 2012; 18: 1394-+.

[90] Zhu C, Anderson AC, Schubart A, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nature Immunology. 2005; 6: 1245-1252.

[91] Cao E, Zang X, Ramagopal UA, et al. T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface. Immunity. 2007; 26: 311-321.

[92] DeKruyff RH, Bu X, Ballesteros A, et al. T cell/transmembrane, Ig, and Mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells. J Immunol. 2010; 184: 1918-1930.

[93] Chiba S, Baghdadi M, Akiba H, et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nature Immunology. 2012; 13: 832-842.

[94] Huang Y-H, Zhu C, Kondo Y, et al. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature. 2015; 517: 386-U566.

[95] Sabatos-Peyton CA, Nevin J, Brock A, et al. Blockade of Tim-3 binding to phosphatidylserine and CEACAM1 is a shared feature of anti-Tim-3 antibodies that have functional efficacy. Oncoimmunology. 2018; 7: e1385690.

[96] Clayton KL, Haaland MS, Douglas-Vail MB, et al. T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases. J Immunol. 2014; 192: 782-791.

[97] van de Weyer PS, Muehlfeit M, Klose C, Bonventre JV, Walz G, Kuehn EW. A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9. Biochem Bioph Res Co. 2006; 351: 571-576.

[98] Davidson D, Schraven B, Veillette A. PAG-associated FynT regulates calcium signaling and promotes anergy in T lymphocytes. Mol Cell Biol. 2007; 27: 1960-1973.

[99] Kikushige Y. TIM-3 in normal and malignant hematopoiesis: structure, function, and signaling pathways. Cancer Sci. 2021; 112: 3419-3426.

[100] Escobar G, Mangani D, Anderson AC. T cell factor 1: a master regulator of the T cell response in disease. Sci Immunol. 2020; 5: eabb9726.

[101] Jin H-T, Anderson AC, Tan WG, et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. P Natl Acad Sci USA. 2010; 107: 14733-14738.

[102] Fourcade J, Sun Z, Pagliano O, et al. PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8 T cells induced by melanoma vaccines. Cancer Res. 2014; 74: 1045-1055.

[103] Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010; 207: 2187-2194.

[104] Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8 T cell dysfunction in melanoma patients. J Exp Med. 2010; 207: 2175-2186.

[105] Dardalhon V, Anderson AC, Karman J, et al. Tim-3/Galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b Ly-6G myeloid cells. J Immunol. 2010; 185: 1383-1392.

[106] Gao X, Zhu Y, Li G, et al. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. Plos One. 2012; 7: e30676.

[107] Sakuishi K, Ngiow SF, Sullivan JM, et al. TIM3 FOXP3 regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Oncoimmunology. 2013; 2: e23849.

[108] Li H, Wu K, Tao K, et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology. 2012; 56: 1342-1351.

[109] Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity. 2016; 44: 989-1004.

[110] Fu Z, Liu H, Wang L, et al. A reporter gene assay for determining the biological activity of therapeutic antibodies targeting TIGIT. Acta Pharm Sin B. 2021; 11: 3925-3934.

[111] Reches A, Ophir Y, Stein N, et al. Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity. Journal for Immunotherapy of Cancer. 2020; 8: e000266.

[112] Yu X, Harden K, C Gonzalez L, et al. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nature Immunology. 2009; 10: 48-57.

[113] Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. P Natl Acad Sci USA. 2009; 106: 17858-17863.

[114] Lepletier A, Madore J, O'Donnell JS, et al. Tumor CD155 expression is associated with resistance to anti-PD1 immunotherapy in metastatic melanoma. Clin Cancer Res. 2020; 26: 3671-3681.

[115] Sun H, Huang Q, Huang M, et al. Human CD96 correlates to natural killer cell exhaustion and predicts the prognosis of human hepatocellular carcinoma. Hepatology. 2019; 70: 168-183.

[116] Freed-Pastor WA, Lambert LJ, Ely ZA, et al. The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer. Cancer Cell. 2021; 39: 1342-+.

[117] Stengel KF, Harden-Bowles K, Yu X, et al. Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires—receptor clustering. P Natl Acad Sci USA. 2012; 109: 5399-5404.

[118] Liu S, Zhang H, Li M, et al. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ. 2013; 20: 456-464.

[119] Johnston RJ, Comps-Agrar L, Hackney J, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8 T cell effector function. Cancer Cell. 2014; 26: 923-937.

[120] Joller N, Lozano E, Burkett PR, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014; 40: 569-581.

[121] Kurtulus S, Sakuishi K, Ngiow S-F, et al. TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest. 2015; 125: 4053-4062.

[122] Chauvin J-M, Pagliano O, Fourcade J, et al. TIGIT and PD-1 impair tumor antigen-specific CD8 T cells in melanoma patients. J Clin Invest. 2015; 125: 2046-2058.

[123] Fourcade J, Sun Z, Chauvin J-M, et al. CD226 opposes TIGIT to disrupt Tregs in melanoma. Jci Insight. 2018; 3: e121157.

[124] Wojciechowicz K, Spodzieja M, Wardowska A. The BTLA-HVEM complex—The future of cancer immunotherapy. Eur J Med Chem. 2024; 268: 116231.

[125] Ding C, Zhang Y, Xia T, et al. Perioperative the BTLA inhibitor (tifcemalimab) combined with toripalimab and chemotherapy for resectable locally advanced thoracic esophageal squamous cell carcinoma trial (BT-NICE trial): a prospective, single-arm, exploratory study. Front Immunol. 2025; 16: 1542877.

[126] Guruprasad P, Carturan A, Zhang Y, et al. The BTLA-HVEM axis restricts CAR T cell efficacy in cancer. Nat Immunol. 2024; 25: 1020-1032.

[127] Park J-E, Brand DD, Rosloniec EF, et al. Leukocyte-associated immunoglobulin-like receptor 1 inhibits T-cell signaling by decreasing protein phosphorylation in the T-cell signaling pathway. J Biol Chem. 2020; 295: 2239-2247.

[128] Cao Q, Fu A, Yang S, et al. Leukocyte-associated immunoglobulin-like receptor-1 expressed in epithelial ovarian cancer cells and involved in cell proliferation and invasion. Biochem Biophys Res Commun. 2015; 458: 399-404.

[129] Yang L-L, Zhang M-J, Wu L, et al. LAIR-1 overexpression and correlation with advanced pathological grade and immune suppressive status in oral squamous cell carcinoma. Head Neck. 2019; 41: 1080-1086.

[130] Xu L, Wang S, Li J, Li J, Li B. Cancer immunotherapy based on blocking immune suppression mediated by an immune modulator LAIR-1. Oncoimmunology. 2020; 9: 1740477.

[131] Wei X, Pan S, Wang Z, et al. LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines. Cell Death Dis. 2023; 14: 684.

[132] Wang J, Wu G, Manick B, et al. VSIG-3 as a ligand of VISTA inhibits human T-cell function. Immunology. 2019; 156: 74-85.

[133] Johnston RJ, Su LJ, Pinckney J, et al. VISTA is an acidic pH-selective ligand for PSGL-1. Nature. 2019; 574: 565-+.

[134] Kakavand H, Jackett LA, Menzies AM, et al. Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod Pathol. 2017; 30: 1666-1676.

[135] Musielak B, Kocik J, Skalniak L, et al. CA-170 - a potent small-molecule PD-L1 inhibitor or not?. Molecules. 2019; 24.

[136] Ta HM, Roy D, Zhang K, et al. LRIG1 engages ligand VISTA and impairs tumor-specific CD8(+) T cell responses. Sci Immunol. 2024; 9: eadi7418.

[137] Vanmeerbeek I, Naulaerts S, Sprooten J, et al. Targeting conserved TIM3(+)VISTA(+) tumor-associated macrophages overcomes resistance to cancer immunotherapy. Sci Adv. 2024; 10: eadm8660.

[138] Zhang YY, Zhang ZM. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020; 17: 807-821.

[139] Chow A, Perica K, Klebanoff CA, Wolchok JD. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat Rev Clin Oncol. 2022; 19: 775-790.

[140] Zinn S, Vazquez-Lombardi R, Zimmermann C, Sapra P, Jermutus L, Christ D. Advances in antibody-based therapy in oncology. Nat Cancer. 2023; 4: 165-180.

[141] Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma (vol 363, pg 711, 2010). New Engl J Med. 2010; 363: 1290-1290.

[142] Cameron F, Whiteside G, Perry C. Ipilimumab: first global approval. Drugs. 2011; 71: 1093-1104.

[143] Blank CU, Lucas MW, Scolyer RA, et al. Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma. N Engl J Med. 2024; 391: 1696-1708.

[144] Keam SJ. Tremelimumab: first approval. Drugs. 2023; 83: 93-102.

[145] Sangro B, Galle PR, Kelley RK, et al. Patient-reported outcomes from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2024; 42.

[146] Johnson ML, Cho BC, Luft A, et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: the phase III POSEIDON study. J Clin Oncol. 2023; 41: 1213-+.

[147] Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009; 114: 1537-1544.

[148] Chapon M, Randriamampita C, Maubec E, et al. Progressive upregulation of PD-1 in primary and metastatic melanomas associated with blunted TCR signaling in infiltrating T lymphocytes. J Invest Dermatol. 2011; 131: 1300-1307.

[149] Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. New Engl J Med. 2019; 381: 1535-1546.

[150] Schmid P, Cortes J, Dent R, et al. Overall survival with pembrolizumab in early-stage triple-negative breast cancer. The New England journal of medicine. 2024.

[151] Keam SJ. Toripalimab: first Global Approval. Drugs. 2019; 79: 573-578.

[152] Lu S, Zhang W, Wu L, et al. Perioperative toripalimab plus chemotherapy for patients with resectable non-small cell lung cancer: the neotorch randomized clinical trial. JAMA. 2024; 331: 201-211.

[153] Hoy SM. Sintilimab: first global approval. Drugs. 2019; 79: 341-346.

[154] Xu J, Jiang H, Pan Y, et al. Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: the ORIENT-16 randomized clinical trial. JAMA. 2023; 330: 2064-2074.

[155] Markham A, Duggan S. Cemiplimab: first global approval. Drugs. 2018; 78: 1841-1846.

[156] Lewis KD, Peris K, Sekulic A, et al. Final analysis of phase II results with cemiplimab in metastatic basal cell carcinoma after hedgehog pathway inhibitors. Ann Oncol. 2024; 35: 221-228.

[157] Sezer A, Kilickap S, Gümüş M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021; 397: 592-604.

[158] Lee A, Keam SJ. Tislelizumab: first Approval. Drugs. 2020; 80: 617-624.

[159] Qiu M-Z, Oh D-Y, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: rATIONALE-305 randomised, double blind, phase 3 trial. Bmj-Brit Med J. 2024; 385: e078876.

[160] Markham A, Keam SJ. Camrelizumab: first global approval. Drugs. 2019; 79: 1355-1361.

[161] Lin ZY, Zhang P, Chi P, et al. Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial. Ann Oncol. 2024; 35: 882-891.

[162] Cai H, Lin J, Zhu H, Zheng Z. Camrelizumab plus rivoceranib compared sorafenib as first-line therapeutic options for advanced hepatocellular carcinoma in China: a cost-effectiveness analysis. BMJ Open. 2024; 14: e079603.

[163] Zhou C, Chen G, Huang Y, et al. Camrelizumab plus carboplatin and pemetrexed as first-line therapy for advanced non-squamous non-small-cell lung cancer: 5-year outcomes of the CameL randomized phase 3 study. J Immunother Cancer. 2024; 12.

[164] Dhillon S. Penpulimab: first approval. Drugs. 2021; 81: 2159-2166.

[165] Markham A. Zimberelimab: first approval. Drugs. 2021; 81: 2063-2068.

[166] Markham A. Atezolizumab: first global approval. Drugs. 2016; 76: 1227-1232.

[167] Lee SM, Schulz C, Prabhash K, et al. First-line atezolizumab monotherapy versus single-agent chemotherapy in patients with non-small-cell lung cancer ineligible for treatment with a platinum-containing regimen (IPSOS): a phase 3, global, multicentre, open-label, randomised controlled study. Lancet. 2023; 402: 451-463.

[168] Piscaglia F, Masi G, Martinelli E, et al. Atezolizumab plus bevacizumab as first-line treatment of unresectable hepatocellular carcinoma: interim analysis results from the phase IIIb AMETHISTA trial. ESMO Open. 2025; 10: 104110.

[169] Syed YY. Durvalumab: first global approval. Drugs. 2017; 77: 1369-1376.

[170] Cheng Y, Spigel DR, Cho BC, et al. Durvalumab after chemoradiotherapy in limited-stage small-cell lung cancer. N Engl J Med. 2024; 391: 1313-1327.

[171] Kim ESA. First global approval. Drugs. 2017; 77: 929-937.

[172] Grivas P, Park SH, Voog E, et al. Avelumab first-line maintenance therapy for advanced urothelial carcinoma: comprehensive clinical subgroup analyses from the JAVELIN bladder 100 phase 3 trial. Eur Urol. 2023; 84: 95-108.

[173] Dhillon S, Duggan SS. First approval. Drugs. 2022; 82: 593-599.

[174] Zhou C, Wang Z, Sun M, et al. Interim survival analysis of the randomized phase III GEMSTONE-302 trial: sugemalimab or placebo plus chemotherapy as first-line treatment for metastatic NSCLC. Nat Cancer. 2023; 4: 860-871.

[175] Zhang X, Wang J, Wang G, et al. LBA79 GEMSTONE-303: prespecified progression-free survival (PFS) and overall survival (OS) final analyses of a phase III study of sugemalimab plus chemotherapy vs placebo plus chemotherapy in treatment-naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Ann Oncol. 2023; 34: S1319.

[176] Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. New Engl J Med. 2022; 386: 24-34.

[177] Ascierto PA, Lipson EJ, Dummer R, et al. 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. 2023; 41: 2724-+.

[178] Merck Provides Update on Phase 3 KEYFORM-007 Trial Evaluating Investigational Fixed-Dose Combination of Favezelimab and Pembrolizumab for Patients With Previously Treated PD-L1 Positive Microsatellite Stable Metastatic Colorectal Cancer, < https://www.merck.com/news/merck-provides-update-on-phase-3-keyform-007-trial-evaluating-investigational-fixed-dose-combination-of-favezelimab-and-pembrolizumab-for-patients-with-previously-treated-pd-l1-positive-microsatellite/>(2024).

[179] Rudin CM, Liu SV, Soo RA, et al. SKYSCRAPER-02: primary results of a phase III, randomized, double-blind, placebo-controlled study of atezolizumab (atezo) plus carboplatin plus etoposide (CE) with or without tiragolumab (tira) in patients (pts) with untreated extensive-stage small cell lung cancer (ES-SCLC). J Clin Oncol. 2022; 40.

[180] Shapira-Frommer R, Niu J, Perets R, et al. The KEYVIBE program: vibostolimab and pembrolizumab for the treatment of advanced malignancies. Future Oncol. 2024; 20: 1983-1991.

[181] Frentzas S, Kao S, Gao R, et al. 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. Journal for Immunotherapy of Cancer. 2023; 11: e005829.

[182] Rodriguez-Abreu D, Bosch-Barrera J, Gray JE, et al. STAR-121: a phase III randomized study of domvanalimab and zimberelimab in combination with chemotherapy versus pembrolizumab with chemotherapy in untreated metastatic non-small cell lung cancer with no actionable gene alterations. Clin Lung Cancer. 2024; 25: 274-279.

[183] Cai LT, Li YC, Tan JX, Xu L, Li YQ. Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy. J Hematol Oncol. 2023; 16.

[184] Lakhani N, Spreafico A, Tolcher AW, et al. Phase I studies of Sym021, an anti-PD-1 antibody, alone and in combination with Sym022 (anti-LAG-3) or Sym023 (anti-TIM-3). Ann Oncol. 2020; 31: S704-S704.

[185] Gutierrez ME, Tang S-C, Powderly JD, et al. First-in-human phase I study of INCAGN02390, a TIM-3 monoclonal antibody antagonist in patients with advanced malignancies. Ann Oncol. 2022; 33: S876-S877.

[186] Curigliano G, Gelderblom H, Mach N, et al. Phase I/Ib clinical trial of sabatolimab, an anti-TIM-3 antibody, alone and in combination with spartalizumab, an anti-PD-1 antibody, in advanced solid tumors. Clin Cancer Res. 2021; 27: 3620-3629.

[187] Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. New Engl J Med. 2016; 375: 819-829.

[188] Koyama S, Akbay EA, Li YY, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016; 7.

[189] Gao J, Ward JF, Pettaway CA, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nature Medicine. 2017; 23: 551-+.

[190] Masatoshi Kudo TY, Decaens T, Sangro B, et al. 2025 ASCO Gastrointestinal Cancers Symposium. Journal of Clinical Oncology; 2025. in. suppl.

[191] Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al. Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma. New Engl J Med. 2025; 392.

[192] Paolo Antonio Ascierto RD, Gaudy-Marqueste C, Bowyer S, et al. Evan J. Lipson, Eleonora Ghisoni, Mark R. Middleton, Barbara Ratto, William Joseph Jackson, Alicia Cheong, Sourav Mukherjee, Jenny Wu, and Georgina V. Long Vol. Volume 42, Number 16_suppl. (Journal of Clinical Oncology, Chicago, 2024)

[193] Schuler M, Cuppens K, Plönes T, et al. Neoadjuvant nivolumab with or without relatlimab in resectable non-small-cell lung cancer: a randomized phase 2 trial. Nature Medicine. 2024; 30.

[194] Liu SV, Dziadziuszko R, Sugawara S, et al. Five-year survival in patients with ES-SCLC treated with atezolizumab in IMpower133: imbrella a extension study results. J Thorac Oncol. 2023; 18: S44-S45.

[195] Wang Z-X, Cui C, Yao J, et al. Toripalimab plus chemotherapy in treatment-naive, advanced esophageal squamous cell carcinoma (JUPITER-06): a multi-center phase 3 trial. Cancer Cell. 2022; 40: 277-+.

[196] Quezada SA. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006; 116: 1935-1945.

[197] Xia L, Tian E, Yu M, et al. RORγt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers. J Exp Clin Canc Res. 2022; 41: 155.

[198] Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. Journal for immunotherapy of cancer. 2014; 2: 3-3.

[199] Sharma P, Hu-Lieskovan S, Wargo JA, Ribas AP. Adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017; 168: 707-723.

[200] Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020; 21: 1563-1573.

[201] Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med. 2022; 386: 437-448.

[202] Merck and Eisai Provide Update on Phase 3 Trials of KEYTRUDA® (pembrolizumab) Plus LENVIMA® (lenvatinib) In Certain Patients With Advanced Melanoma (LEAP-003) and Metastatic Colorectal Cancer (LEAP-017), 2023.

[203] Neal J, Pavlakis N, Kim S-W, et al. CONTACT-01: a randomized phase III trial of atezolizumab + cabozantinib versus docetaxel for metastatic non-small cell lung cancer after a checkpoint inhibitor and chemotherapy. J Clin Oncol. 2024; 42: 2393-2403.

[204] Lybaert L, Lefever S, Fant B, et al. Challenges in neoantigen-directed therapeutics. Cancer Cell. 2023; 41: 15-40.

[205] Klein C, Brinkmann U, Reichert JM, Kontermann RE. The present and future of bispecific antibodies for cancer therapy. Nat Rev Drug Discov. 2024; 23: 301-319.

[206] Dhillon S. Tarlatamab: first approval. Drugs. 2024; 84: 995-1003.

[207] HARMONi-A Study Investigators, Fang W, Zhao Y, et al. Ivonescimab plus chemotherapy in non-small cell lung cancer with EGFR variant: a randomized clinical trial. JAMA. 2024; 332: 561-570.

[208] Andrade PEA, Manucci PM, Kessler CM. Emicizumab: the hemophilia A game-changer. Haematologica. 2024; 109: 1334-1347.

[209] Shirley M. Faricimab: first approval. Drugs. 2022; 82: 825-830.

[210] Keam SJ. Ozoralizumab: first approval. Drugs. 2023; 83: 87-92.

[211] Keam SJ. Cadonilimab: first approval. Drugs. 2022; 82: 1333-1339.

[212] Wu X, Sun Y, Yang H, et al. Cadonilimab plus platinum-based chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer (COMPASSION-16): a randomised, double-blind, placebo-controlled phase 3 trial in China. Lancet. 2024; 404: 1668-1676.

[213] Shen L, Zhang Y, Ziyu L, et al. First-line cadonilimab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma: a randomized, double-blind, phase 3 trial. Nat Med. 2025.

[214] Luke JJ, Patel MR, Blumenschein GR, et al. The PD-1-and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial. Nature Medicine. 2023.

[215] Lan Y, Zhang D, Xu C, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med. 2018; 10: eaan5488.

[216] Sievers C, Craveiro M, Friedman J, et al. Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer. Cancer Cell. 2023; 41: 887-+.

[217] Magdalena Fay CS, Robbins Y, Yang X, et al. TGF-b neutralization attenuates tumor residency of activated T cells to enhance systemic immunity in mice. iScience. 2024; 27(8): 110520.

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