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Abstract: Dysfunction of anti-tumor immune responses is crucial for cancer progression. immune checkpoint blockade (ICB), which can potentiate T cell responses, is an effective strategy for the normalization of host anti-tumor immunity. In recent years, immune checkpoints, expressed on both tumor cells and immune cells, have been identified; some of them have exhibited potential druggability and have been approved by the US Food and Drug Administration (FDA) for clinical treatment. However, limited responses and immune-related adverse events (irAEs) cannot be ignored. This review outlines the development and applications of ICBs, potential strategies for overcoming resistance, and future directions for ICB-based cancer immunotherapy.

免疫检查点阻断的癌症治疗：最新进展与展望

[1]Abu-SbeihH, AliFS, QiaoW, et al., 2019. Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma. Cancer Immunol Immunother, 68(4):553-561.

[2]AdvaniR, FlinnI, PopplewellL, et al., 2018. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N Engl J Med, 379(18):1711-1721.

[3]AggarwalC, PrawiraA, AntoniaS, et al., 2022. Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial. J Immunother Cancer, 10(4):e004424.

[4]AhnM, 2018. MS28.02 Combination IO+IO. J Thorac Oncol, 13(10S):S299-S300.

[5]AlmutairiAR, McBrideA, SlackM, et al., 2020. Potential immune-related adverse events associated with monotherapy and combination therapy of ipilimumab, nivolumab, and pembrolizumab for advanced melanoma: a systematic review and meta-analysis. Front Oncol, 10:91.

[6]AndrewsLP, MarciscanoAE, DrakeCG, et al., 2017. LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev, 276(1):80-96.

[7]AndrewsLP, YanoH, VignaliDAA, 2019. Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups. Nat Immunol, 20(11):1425-1434.

[8]ArredouaniMS, FrancoF, ImrichA, et al., 2007. Scavenger receptors SR-AI/II and MARCO limit pulmonary dendritic cell migration and allergic airway inflammation. J Immunol, 178(9):5912-5920.

[9]AsrirA, TardiveauC, CoudertJ, et al., 2022. Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell, 40(30):318-334.e9.

[10]AttiaP, PhanGQ, MakerAV, et al., 2005. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol, 23(25):6043-6053.

[11]AttrillGH, OwenCN, AhmedT, et al., 2022. Higher proportions of CD39+ tumor-resident cytotoxic T cells predict recurrence-free survival in patients with stage III melanoma treated with adjuvant immunotherapy. J Immunother Cancer, 10(6):e004771.

[12]BallyAPR, LuPY, TangY, et al., 2015. NF-κB regulates PD-1 expression in macrophages. J Immunol, 194(9):4545-4554.

[13]BarkalAA, WeiskopfK, KaoKS, et al., 2018. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat Immunol, 19(1):76-84.

[14]BarruetoL, CamineroF, CashL, et al., 2020. Resistance to checkpoint inhibition in cancer immunotherapy. Transl Oncol, 13(3):100738.

[15]BenciJL, XuBH, QiuY, et al., 2016. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell, 167(6):1540-1554.e12.

[16]BorcomanE, KanjanapanY, ChampiatS, et al., 2019. Novel patterns of response under immunotherapy. Ann Oncol, 30(3):385-396.

[17]BrahmerJR, LacchettiC, SchneiderBJ, et al., 2018. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol, 36(17):1714-1768.

[18]BriukhovetskaD, DörrJ, EndresS, et al., 2021. Interleukins in cancer: from biology to therapy. Nat Rev Cancer, 21(8):481-499.

[19]BurshtynDN, MorcosC, 2016. The expanding spectrum of ligands for leukocyte Ig-like receptors. J Immunol, 196(3):947-955.

[20]CasadoJG, PawelecG, MorgadoS, et al., 2009. Expression of adhesion molecules and ligands for activating and costimulatory receptors involved in cell-mediated cytotoxicity in a large panel of human melanoma cell lines. Cancer Immunol Immunother, 58(9):1517-1526.

[21]CastroF, CardosoAP, GonçalvesRM, et al., 2018. Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Front Immunol, 9:847.

[22]CeerazS, NowakEC, NoelleRJ, 2013. B7 family checkpoint regulators in immune regulation and disease. Trends Immunol, 34(11):556-563.

[23]ChampiatS, DercleL, AmmariS, et al., 2017. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res, 23(8):1920-1928.

[24]ChapovalAI, NiJ, LauJS, et al., 2001. B7-H3: a costimulatory molecule for T cell activation and IFN-γ production. Nat Immunol, 2(3):269-274.

[25]ChenDS, MellmanI, 2017. Elements of cancer immunity and the cancer‒immune set point. Nature, 541(7637):321-330.

[26]ChenGY, TangJ, ZhengP, et al., 2009. CD24 and Siglec-10 selectively repress tissue damage‒induced immune responses. Science, 323(5922):1722-1725.

[27]ChenGY, ChenX, KingS, et al., 2011. Amelioration of sepsis by inhibiting sialidase-mediated disruption of the CD24-siglecg interaction. Nat Biotechnol, 29(5):428-435.

[28]ChenLP, FliesDB, 2013. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol, 13(4):227-242.

[29]CheungTC, OborneLM, SteinbergMW, et al., 2009. T cell intrinsic heterodimeric complexes between HVEM and BTLA determine receptivity to the surrounding microenvironment. J Immunol, 183(11):7286-7296.

[30]ChibaS, BaghdadiM, AkibaH, et al., 2012. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat Immunol, 13(9):832-842.

[31]ChoiIH, ZhuGF, SicaGL, et al., 2003. Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. J Immunol, 171(9):4650-4654.

[32]ChowellD, MorrisLGT, GriggCM, et al., 2018. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science, 359(6375):582-587.

[33]DasM, ZhuC, KuchrooVK, 2017. TIM-3 and its role in regulating anti-tumor immunity. Immunol Rev, 276(1):97-111.

[34]DavarD, BoasbergPD, ErogluZ, et al., 2018. A phase 1 study of TSR-022, an anti-TIM-3 monoclonal antibody, in combination with TSR-042 (anti-PD-1) in patients with colorectal cancer and post-PD-1 NSCLC and melanoma. J Immunother Therapy Cancer, 6(S1):S115.

[35]DixonKO, TabakaM, SchrammMA, et al., 2021. TIM-3 restrains anti-tumour immunity by regulating inflammasome activation. Nature, 595(7865):101-106.

[36]DolladilleC, EderhyS, SassierM, et al., 2020. Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer. JAMA Oncol, 6(6):865-871.

[37]DongHD, StromeSE, SalomaoDR, et al., 2002. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med, 8(8):793-800.

[38]DowneySG, KlapperJA, SmithFO, et al., 2007. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res, 13(22 Pt 1):6681-6688.

[39]DunnGP, BruceAT, IkedaH, et al., 2002. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol, 3(11):991-998.

[40]EltanboulyMA, SchaafsmaE, NoelleRJ, et al., 2020. VISTA: coming of age as a multi-lineage immune checkpoint. Clin Exp Immunol, 200(2):120-130.

[41]FicialM, JegedeOA, Sant'AngeloM, et al., 2021. Expression of T-cell exhaustion molecules and human endogenous retroviruses as predictive biomarkers for response to nivolumab in metastatic clear cell renal cell carcinoma. Clin Cancer Res, 27(5):1371-1380.

[42]FinnRS, QinSK, IkedaM, et al., 2020. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med, 382(20):1894-1905.

[43]FliesDB, HanX, HiguchiT, et al., 2014. Coinhibitory receptor PD-1H preferentially suppresses CD4⁺ T cell-mediated immunity. J Clin Invest, 124(5):1966-1975.

[44]FourcadeJ, SunZJ, BenallaouaM, et al., 2010. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen‒specific CD8⁺ T cell dysfunction in melanoma patients. J Exp Med, 207(10):2175-2186.

[45]FranciscoLM, SagePT, SharpeAH, 2010. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev, 236(1):219-242.

[46]Fresno Vara JÁ, CasadoE, de CastroJ, et al., 2004. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev, 30(2):193-204.

[47]GanesanS, MehnertJ, 2020. Biomarkers for response to immune checkpoint blockade. Annu Rev Cancer Biol, 4(1):331-351.

[48]GaoX, ZhuYB, LiG, et al., 2012. TIM-3 expression characterizes regulatory T cells in tumor tissues and is associated with lung cancer progression. PLoS ONE, 7(2):e30676.

[49]GavrieliM, WatanabeN, LoftinSK, et al., 2003. Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and SHP-2. Biochem Biophys Res Commun, 312(4):1236-1243.

[50]GeraudA, GougisP, VozyA, et al., 2021. Clinical pharmacology and interplay of immune checkpoint agents: a Yin-Yang balance. Annu Rev Pharmacol Toxicol, 61:85-112.

[51]GoelS, DecristoMJ, WattAC, et al., 2017. CDK4/6 inhibition triggers anti-tumour immunity. Nature, 548(7668):471-475.

[52]Gomes de MoraisAL, CerdáS, de MiguelM, 2022. New checkpoint inhibitors on the road: targeting TIM-3 in solid tumors. Curr Oncol Rep, 24(5):651-658.

[53]GonzalezLC, LoyetKM, Calemine-FenauxJ, et al., 2005. A coreceptor interaction between the CD28 and TNF receptor family members B and T lymphocyte attenuator and herpesvirus entry mediator. Proc Natl Acad Sci USA, 102(4):1116-1121.

[54]GrassoCS, TsoiJ, OnyshchenkoM, et al., 2020. Conserved interferon-γ signaling drives clinical response to immune checkpoint blockade therapy in melanoma. Cancer Cell, 38(4):500-515.e3.

[55]HallET, SinghalS, DickersonJ, et al., 2019. Patient-reported outcomes for cancer patients receiving checkpoint inhibitors: opportunities for palliative care—a systematic review. J Pain Symptom Manage, 58(1):137-156.e1.

[56]HanP, GoularteOD, RufnerK, et al., 2004. An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection. J Immunol, 172(10):5931-5939.

[57]HannierS, TournierM, BismuthG, et al., 1998. CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling. J Immunol, 161(8):4058-4065.

[58]HardingJJ, PatnaikA, MorenoV, et al., 2019. A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): interim safety, efficacy, and pharmacokinetic findings in advanced cancers. J Clin Oncol, 37(8):12-12.

[59]HardingJJ, MorenoV, BangYJ, et al., 2021. Blocking TIM-3 in treatment-refractory advanced solid tumors: a phase Ia/b study of LY3321367 with or without an anti-PD-L1 antibody. Clin Cancer Res, 27(8):2168-2178.

[60]HeldW, MariuzzaRA, 2008. Cis interactions of immunoreceptors with MHC and non-MHC ligands. Nat Rev Immunol, 8(4):269-278.

[61]HiggsBW, MorehouseCA, StreicherK, et al., 2018. Interferon gamma messenger RNA signature in tumor biopsies predicts outcomes in patients with non-small cell lung carcinoma or urothelial cancer treated with durvalumab. Clin Cancer Res, 24(16):3857-3866.

[62]HirayamaS, IshiiG, NagaiK, et al., 2012. Prognostic impact of CD204-positive macrophages in lung squamous cell carcinoma: possible contribution of CD204-positive macrophages to the tumor-promoting microenvironment. J Thorac Oncol, 7(12):1790-1797.

[63]HodiFS, O'DaySJ, McDermottDF, et al., 2010. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med, 363(8):711-723.

[64]HollebecqueA, ChungHC, de MiguelMJ, et al., 2021. Safety and antitumor activity of α-PD-L1 antibody as monotherapy or in combination with α-TIM-3 antibody in patients with microsatellite instability-high/mismatch repair-deficient tumors. Clin Cancer Res, 27(23):6393-6404.

[65]HoltzhausenA, ZhaoF, EvansKS, et al., 2015. Melanoma-derived Wnt5a promotes local dendritic-cell expression of IDO and immunotolerance: opportunities for pharmacologic enhancement of immunotherapy. Cancer Immunol Res, 3(9):1082-1095.

[66]Hone LopezS, JalvingM, FehrmannRSN, et al., 2022. The gut wall’s potential as a partner for precision oncology in immune checkpoint treatment. Cancer Treat Rev, 107:102406.

[67]HuangCT, WorkmanCJ, FliesD, et al., 2004. Role of LAG-3 in regulatory T cells. Immunity, 21(4):503-513.

[68]HuangX, ZhangXZ, LiEL, et al., 2020. VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy. J Hematol Oncol, 13:83.

[69]HuangYH, ZhuC, KondoY, et al., 2015. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. Nature, 517(7534):386-390.

[70]HurchlaMA, SedyJR, GavrielliM, et al., 2005. B and T lymphocyte attenuator exhibits structural and expression polymorphisms and is highly induced in anergic CD4+ T cells. J Immunol, 174(6):3377-3385.

[71]IivanainenS, AlankoT, VihinenP, et al., 2020. Follow-up of cancer patients receiving anti-PD-(L)1 therapy using an electronic patient-reported outcomes tool (KISS): prospective feasibility cohort study. JMIR Form Res, 4(10):e17898.

[72]IshidaY, AgataY, ShibaharaK, et al., 1992. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J, 11(11):3887-3895.

[73]JanakiramM, ShahUA, LiuWF, et al., 2017. The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3. Immunol Rev, 276(1):26-39.

[74]JohnsonDB, BalkoJM, ComptonML, et al., 2016. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med, 375(18):1749-1755.

[75]JohnstonRJ, SuLJ, PinckneyJ, et al., 2019. VISTA is an acidic pH-selective ligand for PSGL-1. Nature, 574(7779):565-570.

[76]JollerN, HaflerJP, BrynedalB, et al., 2011. Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol, 186(3):1338-1342.

[77]KalbasiA, RibasA, 2020. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol, 20(1):25-39.

[78]KeirME, ButteMJ, FreemanGJ, et al., 2008. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 26:677-704.

[79]KimTK, VandsembEN, HerbstRS, et al., 2022. Adaptive immune resistance at the tumour site: mechanisms and therapeutic opportunities. Nat Rev Drug Discov, 21(7):529-540.

[80]KisielowM, KisielowJ, Capoferri-SollamiG, et al., 2005. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur J Immunol, 35(7):2081-2088.

[81]KokIC, HooiveldJS, van de DonkPP, et al., 2022. ⁸⁹Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer. Ann Oncol, 33(1):80-88.

[82]KontosF, MichelakosT, KurokawaT, et al., 2021. B7-H3: an attractive target for antibody-based immunotherapy. Clin Cancer Res, 27(5):1227-1235.

[83]KrijgsmanO, KemperK, BoshuizenJ, et al., 2021. Predictive immune-checkpoint blockade classifiers identify tumors responding to inhibition of PD-1 and/or CTLA-4. Clin Cancer Res, 27(19):5389-5400.

[84]KurokiK, FurukawaA, MaenakaK, 2012. Molecular recognition of paired receptors in the immune system. Front Microbiol, 3:429.

[85]LeDT, UramJN, WangH, et al., 2015. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med, 372(26):2509-2520.

[86]LevinSD, TaftDW, BrandtCS, et al., 2011. Vstm3 is a member of the CD28 family and an important modulator of T-cell function. Eur J Immunol, 41(4):902-915.

[87]LiB, ChanHL, ChenPP, 2019. Immune checkpoint inhibitors: basics and challenges. Curr Med Chem, 26(17):3009-3025.

[88]LiC, ZhanYD, MaXZ, et al., 2020. B7-H4 facilitates proliferation and metastasis of colorectal carcinoma cell through PI3K/Akt/mTOR signaling pathway. Clin Exp Med, 20(1):79-86.

[89]LiHX, van der MerwePA, SivakumarS, 2022. Biomarkers of response to PD-1 pathway blockade. Br J Cancer, 126(12):1663-1675.

[90]LiHY, PiaoL, LiuSC, et al., 2020. B7-H4 is a potential prognostic biomarker of prostate cancer. Exp Mol Pathol, 114:104406.

[91]LiJ, LeeY, LiYJ, et al., 2018. Co-inhibitory molecule B7 superfamily member 1 expressed by tumor-infiltrating myeloid cells induces dysfunction of anti-tumor CD8⁺ T cells. Immunity, 48(4):773-786.e5.

[92]LiM, XiaPY, DuY, et al., 2014. T-cell immunoglobulin and ITIM domain (TIGIT) receptor/poliovirus receptor (PVR) ligand engagement suppresses interferon-γ production of natural killer cells via β-arrestin 2-mediated negative signaling. J Biol Chem, 289(25):17647-17657.

[93]LiT, LiXY, ZamaniA, et al., 2020. c-Rel is a myeloid checkpoint for cancer immunotherapy. Nat Cancer, 1(5):507-517.

[94]LiXM, XuZG, CuiGY, et al., 2020. BTLA expression in stage I-III non-small-cell lung cancer and its correlation with PD-1/PD-L1 and clinical outcomes. Onco Targets Ther, 13:215-224.

[95]LinesJL, PantaziE, MakJ, et al., 2014a. VISTA is an immune checkpoint molecule for human T cells. Cancer Res, 74(7):1924-1932.

[96]LinesJL, SempereLF, BroughtonT, et al., 2014b. VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res, 2(6):510-517.

[97]LinsleyPS, BradshawJ, GreeneJ, et al., 1996. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity, 4(6):535-543.

[98]LiuS, ZhangH, LiM, et al., 2013. Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell Death Differ, 20(3):456-464.

[99]LiuYT, SunZJ, 2021. Turning cold tumors into hot tumors by improving T-cell infiltration. Theranostics, 11(11):5365-5386.

[100]LoyetKM, OuyangWJ, EatonDL, et al., 2005. Proteomic profiling of surface proteins on Th1 and Th2 cells. J Proteome Res, 4(2):400-409.

[101]LuoN, NixonMJ, Gonzalez-EricssonPI, et al., 2018. DNA methyltransferase inhibition upregulates MHC-I to potentiate cytotoxic T lymphocyte responses in breast cancer. Nat Commun, 9:248.

[102]MaJ, SongYQ, XieY, et al., 2022. Phase I study of the anti-BTLA antibody tifcemalimab as a single agent or in combination with toripalimab in relapsed/refractory lymphomas. Blood, 140(S1):3716-3717.

[103]MaR, LiZL, ChioccaEA, et al., 2023. The emerging field of oncolytic virus-based cancer immunotherapy. Trends Cancer, 9(2):122-139.

[104]MacauleyMS, CrockerPR, PaulsonJC, 2014. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol, 14(10):653-666.

[105]MahadevanNR, KnelsonEH, WolffJO, et al., 2021. Intrinsic immunogenicity of small cell lung carcinoma revealed by its cellular plasticity. Cancer Discov, 11(8):1952-1969.

[106]MarijtKA, SluijterM, BlijlevenL, et al., 2019. Metabolic stress in cancer cells induces immune escape through a PI3K-dependent blockade of IFNγ receptor signaling. J Immunother Cancer, 7(1):152.

[107]MartinezGJ, PereiraRM, ÄijöT, et al., 2015. The transcription factor NFAT promotes exhaustion of activated CD8⁺ T cells. Immunity, 42(2):265-278.

[108]MartinsF, SofiyaL, SykiotisGP, et al., 2019. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol, 16(9):563-580.

[109]MendelsohnCL, WimmerE, RacanielloVR, 1989. Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell, 56(5):855-865.

[110]MerchantYP, MehtaV, Aaqib ShamimM, et al., 2023. Cost-benefit analysis of immune checkpoint inhibitors: is the price worth their value? Oral Oncol, 146:106560.

[111]Meric-BernstamF, LarkinJ, TaberneroJ, et al., 2021. Enhancing anti-tumour efficacy with immunotherapy combinations. Lancet, 397(10278):1010-1022.

[112]MettuNB, UlahannanSV, BendellJC, et al., 2022. A phase 1a/b open-label, dose-escalation study of etigilimab alone or in combination with nivolumab in patients with locally advanced or metastatic solid tumors. Clin Cancer Res, 28(5):882-892.

[113]M'HidiH, ThibultML, ChetailleB, et al., 2009. High expression of the inhibitory receptor BTLA in T-follicular helper cells and in B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Am J Clin Pathol, 132(4):589-596.

[114]ModakS, ZanzonicoP, GrkovskiM, et al., 2020. B7H3-directed intraperitoneal radioimmunotherapy with radioiodinated omburtamab for desmoplastic small round cell tumor and other peritoneal tumors: results of a phase I study. J Clin Oncol, 38(36):4283-4291.

[115]MonneyL, SabatosCA, GagliaJL, et al., 2002. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature, 415(6871):536-541.

[116]MoradG, HelminkBA, SharmaP, et al., 2021. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell, 184(21):5309-5337.

[117]MurtazaA, LakenH, da Silva CorreiaJ, et al., 2016. Discovery of TSR-022, a novel, potent anti-human TIM-3 therapeutic antibody. Eur J Cancer, 69(S1):S102.

[118]MusielakB, KocikJ, SkalniakL, et al., 2019. CA-170—a potent small-molecule PD-L1 inhibitor or not? Molecules, 24(15):2804.

[119]NakamuraK, SmythMJ, 2020. Myeloid immunosuppression and immune checkpoints in the tumor microenvironment. Cell Mol Immunol, 17(1):1-12.

[120]NakanishiK, YoshimotoT, TsutsuiH, et al., 2001. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev, 12(1):53-72.

[121]NakayamaM, AkibaH, TakedaK, et al., 2009. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. Blood, 113(16):3821-3830.

[122]NiuJ, Maurice-DrorC, LeeDH, et al., 2021. First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer. Ann Oncol, 33(2):169-180.

[123]NurievaRI, ChungY, HwangD, et al., 2008. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity, 29(1):138-149.

[124]PanelliMC, WhiteR, FosterM, et al., 2004. Forecasting the cytokine storm following systemic interleukin (IL)-2 administration. J Transl Med, 2:17.

[125]PardollDM, 2012. Immunology beats cancer: a blueprint for successful translation. Nat Immunol, 13(12):1129-1132.

[126]ParkSY, KimIS, 2019. Harnessing immune checkpoints in myeloid lineage cells for cancer immunotherapy. Cancer Lett, 452:51-58.

[127]PatilNS, NabetBY, MüllerS, et al., 2022. Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer. Cancer Cell, 40(3):289-300.e4.

[128]PaukenKE, DouganM, RoseNR, et al., 2019. Adverse events following cancer immunotherapy: obstacles and opportunities. Trends Immunol, 40(6):511-523.

[129]PengWY, ChenJQ, LiuCW, et al., 2016. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov, 6(2):202-216.

[130]PicardaE, OhaegbulamKC, ZangXX, 2016. Molecular pathways: targeting B7-H3 (CD276) for human cancer immunotherapy. Clin Cancer Res, 22(14):3425-3431.

[131]PropperDJ, BalkwillFR, 2022. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol, 19(4):237-253.

[132]RadhakrishnanV, BanavaliS, GuptaS, et al., 2019. Excellent CBR and prolonged PFS in non-squamous NSCLC with oral CA-170, an inhibitor of VISTA and PD-L1. Ann Oncol, 30(S5):v494.

[133]ReadyNE, OttPA, HellmannMD, et al., 2020. Nivolumab monotherapy and nivolumab plus ipilimumab in recurrent small cell lung cancer: results from the CheckMate 032 randomized cohort. J Thorac Oncol, 15(3):426-435.

[134]ReckM, Rodríguez-AbreuD, RobinsonAG, et al., 2016. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med, 375(19):1823-1833.

[135]ReckampKL, RedmanMW, DragnevKH, et al., 2022. Phase II randomized study of ramucirumab and pembrolizumab versus standard of care in advanced non-small-cell lung cancer previously treated with immunotherapy-lung-map S1800A. J Clin Oncol, 40(21):2295-2307.

[136]RibasA, WolchokJD, 2018. Cancer immunotherapy using checkpoint blockade. Science, 359(6382):1350-1355.

[137]RobertC, LongGV, BradyB, et al., 2015. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med, 372(4):320-330.

[138]RobertsonMJ, MierJW, LoganT, et al., 2006. Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin Cancer Res, 12(14):4265-4273.

[139]RobertsonMJ, KirkwoodJM, LoganTF, et al., 2008. A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer. Clin Cancer Res, 14(11):3462-3469.

[140]RosenthalR, CadieuxEL, SalgadoR, et al., 2019. Neoantigen-directed immune escape in lung cancer evolution. Nature, 567(7749):479-485.

[141]RotteA, 2019. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. J Exp Clin Cancer Res, 38:255.

[142]RuddCE, TaylorA, SchneiderH, 2009. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev, 229(1):12-26.

[143]Sade-FeldmanM, JiaoYJ, ChenJH, et al., 2017. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat Commun, 8:1136.

[144]SalmiM, KoskinenK, HenttinenT, et al., 2004. Clever-1 mediates lymphocyte transmigration through vascular and lymphatic endothelium. Blood, 104(13):3849-3857.

[145]SanmamedMF, ChenLP, 2018. A paradigm shift in cancer immunotherapy: from enhancement to normalization. Cell, 175(2):313-326.

[146]SansomDM, 2000. CD28, CTLA-4 and their ligands: who does what and to whom? Immunology, 101(2):169-177.

[147]SchöffskiP, TanDSW, MartínM, et al., 2022. Phase I/II study of the LAG-3 inhibitor ieramilimab (LAG525) ± anti-PD-1 spartalizumab (PDR001) in patients with advanced malignancies. J Immunother Cancer, 10(2):e003776.

[148]SedyJR, GavrieliM, PotterKG, et al., 2005. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat Immunol, 6(1):90-98.

[149]SharmaP, Hu-LieskovanS, WargoJA, et al., 2017. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell, 168(4):707-723.

[150]ShigeokaM, UrakawaN, NakamuraT, et al., 2013. Tumor associated macrophage expressing CD204 is associated with tumor aggressiveness of esophageal squamous cell carcinoma. Cancer Sci, 104(8):1112-1119.

[151]Sordo-BahamondeC, Lorenzo-HerreroS, Gonzalez-RodriguezAP, et al., 2021. BTLA/HVEM axis induces NK cell immunosuppression and poor outcome in chronic lymphocytic leukemia. Cancers, 13(8):1766.

[152]SprangerS, BaoRY, GajewskiTF, 2015. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature, 523(7559):231-235.

[153]SrivastavaS, PellosoD, FengHL, et al., 2013. Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin. Cancer Immunol Immunother, 62(6):1073-1082.

[154]StanietskyN, SimicH, ArapovicJ, et al., 2009. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci USA, 106(42):17858-17863.

[155]SullivanRJ, WeberJS, 2022. Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies. Nat Rev Drug Discov, 21(7):495-508.

[156]SumimotoH, ImabayashiF, IwataT, et al., 2006. The BRAF‒MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med, 203(7):1651-1656.

[157]SznolM, PostowMA, DaviesMJ, et al., 2017. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev, 58:70-76.

[158]TanSY, XuY, WangZH, et al., 2020. Tim-3 hampers tumor surveillance of liver-resident and conventional NK cells by disrupting PI3K signaling. Cancer Res, 80(5):1130-1142.

[159]TawbiHA, SchadendorfD, LipsonEJ, et al., 2022. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med, 386(1):24-34.

[160]TopalianSL, TaubeJM, AndersRA, et al., 2016. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer, 16(5):275-287.

[161]TorinoF, CorselloSM, SalvatoriR, 2016. Endocrinological side-effects of immune checkpoint inhibitors. Curr Opin Oncol, 28(4):278-287.

[162]TriebelF, JitsukawaS, BaixerasE, et al., 1990. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med, 171(5):1393-1405.

[163]UpadhayaS, NeftelinovST, HodgeJ, et al., 2022. Challenges and opportunities in the PD1/PDL1 inhibitor clinical trial landscape. Nat Rev Drug Discov, 21(7):482-483.

[164]VirginHW, WherryEJ, AhmedR, 2009. Redefining chronic viral infection. Cell, 138(1):30-50.

[165]VoronT, ColussiO, MarcheteauE, et al., 2015. VEGF-A modulates expression of inhibitory checkpoints on CD8⁺ T cells in tumors. J Exp Med, 212(2):139-148.

[166]WainbergZA, SachdevJC, BauerT, et al., 2019. FPA150 (B7-H4 antibody) phase I update in advanced solid tumours: monotherapy and in combination with pembrolizumab. Ann Oncol, 30(S5):V489.

[167]WangJH, WuGP, ManickB, et al., 2019. VSIG-3 as a ligand of VISTA inhibits human T-cell function. Immunology, 156(1):74-85.

[168]WangL, RubinsteinR, LinesJL, et al., 2011. VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses. J Exp Med, 208(3):577-592.

[169]WangSX, LiYS, LiuZQ, et al., 2023. Efficacy and safety of first-line immune checkpoint inhibitors combined with chemotherapy for extensive-stage small cell lung cancer: a network meta-analysis. Lung Cancer, 178:47-56.

[170]WangXX, BarreraC, BeraK, et al., 2022. Spatial interplay patterns of cancer nuclei and tumor-infiltrating lymphocytes (TILs) predict clinical benefit for immune checkpoint inhibitors. Sci Adv, 8(22):eabn3966.

[171]WatanabeN, GavrieliM, SedyJR, et al., 2003. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol, 4(7):670-679.

[172]WeberJS, KählerKC, HauschildA, 2012. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol, 30(21):2691-2697.

[173]WolchokJD, NeynsB, LinetteG, et al., 2010. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol, 11(2):155-164.

[174]WolchokJD, Chiarion-SileniV, GonzalezR, et al., 2022. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J Clin Oncol, 40(2):127-137.

[175]WolfY, AndersonAC, KuchrooVK, 2020. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol, 20(3):173-185.

[176]WorkmanCJ, VignaliDAA, 2005. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J Immunol, 174(2):688-695.

[177]WorkmanCJ, RiceDS, DuggerKJ, et al., 2002. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur J Immunol, 32(8):2255-2263.

[178]WorkmanCJ, WangY, El KasmiKC, et al., 2009. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J Immunol, 182(4):1885-1891.

[179]WuCY, CaoX, ZhangXJ, 2021. VISTA inhibitors in cancer immunotherapy: a short perspective on recent progresses. RSC Med Chem, 12(10):1672-1679.

[180]XiaoYL, ChenJ, ZhouH, et al., 2022. Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy. Nat Commun, 13:758.

[181]XuC, ChenYP, DuXJ, et al., 2018. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ, 363:k4226.

[182]XuL, YanX, DingWY, 2022. Meta-analysis of efficacy from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Front Oncol, 12:876098.

[183]YaoS, WangSD, ZhuYW, et al., 2009. PD-1 on dendritic cells impedes innate immunity against bacterial infection. Blood, 113(23):5811-5818.

[184]YarchoanM, HopkinsA, JaffeeEM, 2017. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med, 377(25):2500-2501.

[185]YasudaK, NakanishiK, TsutsuiH, 2019. Interleukin-18 in health and disease. Int J Mol Sci, 20(3):649.

[186]YeQ, ShenY, WangX, et al., 2010. Hypermethylation of HLA class I gene is associated with HLA class I down-regulation in human gastric cancer. Tissue Antigens, 75(1):30-39.

[187]YinYZ, ShiLL, YangJ, et al., 2022. B7 family member H4 induces epithelial-mesenchymal transition and promotes the proliferation, migration and invasion of colorectal cancer cells. Bioengineered, 13(1):107-118.

[188]YuX, HardenK, GonzalezLC, et al., 2009. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol, 10(1):48-57.

[189]ZarourHM, 2016. Reversing T-cell dysfunction and exhaustion in cancer. Clin Cancer Res, 22(8):1856-1864.

[190]ZhangRR, WangLM, ShenJJ, 2020. Overexpression of miR-32 inhibits the proliferation and metastasis of ovarian cancer cells by targeting BTLA. Eur Rev Med Pharmacol Sci, 24(9):4671-4678.

[191]ZhouT, DamskyW, WeizmanOE, et al., 2020. IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy. Nature, 583(7817):609-614.

[192]ZhuC, AndersonAC, SchubartA, et al., 2005. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol, 6(12):1245-1252.

[193]ZinggD, Arenas-RamirezN, SahinD, et al., 2017. The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep, 20(4):854-867.