Research progress of immune checkpoint inhibitors in gastric cancer

doi:10.3760/cma.j.cn371439-20250919-00100

Abstract

Abstract:

Gastric cancer is a major disease that poses a serious threat to human health. Currently，the primary treatment methods remain surgery combined with chemotherapy. In recent years，with the deepening of tumor immunology research，immune checkpoint inhibitors have shown significant efficacy in the treatment of gastric cancer. Both monotherapy and combination treatment regimens provide more options for patients with gastric cancer，demonstrating substantial therapeutic potential. Summarizing and discussing the research progress of immune checkpoint inhibitors in gastric cancer can offer new insights for better clinical management of the disease.

Key words: Stomach neoplasms, Immune checkpoint inhibitors, Immunotherapy

Min Xiyun, Ma Zhuaxiji, Guan Quanlin. Research progress of immune checkpoint inhibitors in gastric cancer[J]. Journal of International Oncology, 2026, 53(10): 635-640.

References 49

[1]	孙可欣, 李荔, 王少明, 等. 2024年中国分地区恶性肿瘤流行情况分析[J]. 中华肿瘤杂志, 2026, 48(3): 400-412. DOI: 10.3760/cma.j.cn112152-20260205-00079.
[2]	赫捷, 陈万青, 李兆申, 等. 中国胃癌筛查与早诊早治指南(2022,北京)[J]. 中华肿瘤杂志, 2022, 44(7): 634-666. DOI: 10.3760/cma.j.cn112152-20220617-00430.
[3]	Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial[J]. JAMA Oncol, 2018, 4(5): e180013. DOI: 10.1001/jamaoncol.2018.0013.
[4]	Fashoyin-Aje L, Donoghue M, Chen H, et al. FDA approval summary: pembrolizumab for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma expressing PD-L1[J]. Oncologist, 2019, 24(1): 103-109. DOI: 10.1634/theoncologist.2018-0221. pmid: 30120163
[5]	Shitara K, Özgüroğlu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial[J]. Lancet, 2018, 392(10142): 123-133. DOI: 10.1016/S0140-6736(18)31257-1. pmid: 29880231
[6]	Chen LT, Satoh T, Ryu MH, et al. A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data[J]. Gastric Cancer, 2020, 23(3): 510-519. DOI: 10.1007/s10120-019-01034-7.
[7]	Poniewierska-Baran A, Sobolak K, Niedźwiedzka-Rystwej P, et al. Immunotherapy based on immune checkpoint molecules and immune checkpoint inhibitors in gastric cancer-narrative review[J]. Int J Mol Sci, 2024, 25(12): 6471. DOI: 10.3390/ijms25126471.
[8]	Cai L, Li Y, Tan J, et al. Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy[J]. J Hematol Oncol, 2023, 16(1): 101. DOI: 10.1186/s13045-023-01499-1.
[9]	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)胃癌诊疗指南2025[M]. 北京: 人民卫生出版社, 2025.
[10]	Shah MA, Kennedy EB, Alarcon-Rozas AE, et al. Immunotherapy and targeted therapy for advanced gastroesophageal cancer: ASCO guideline[J]. J Clin Oncol, 2023, 41(7): 1470-1491. DOI: 10.1200/JCO.22.02331.
[11]	Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial[J]. Lancet, 2021, 398(10294): 27-40. DOI: 10.1016/S0140-6736(21)00797-2. pmid: 34102137
[12]	Ha SY, Oh DY, Yañez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double- blind, phase 3 trial[J]. Lancet Oncol, 2023, 24(11): 1181-1195. DOI: 10.1016/S1470-2045(23)00515-6.
[13]	Xu J, Jiang H, Pan Y, et al. Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: the ORIENT-16 randomized clinical trial[J]. JAMA, 2023, 330(21): 2064-2074. DOI: 10.1001/jama.2023.19918. pmid: 38051328
[14]	Qiu MZ, Oh DY, 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[J]. BMJ, 2024, 385: e078876. DOI: 10.1136/bmj-2023-078876.
[15]	Zhang X, Wang J, Wang G, et al. First-Line sugemalimab plus chemotherapy for advanced gastric cancer: the GEMSTONE-303 randomized clinical trial[J]. JAMA, 2025, 333(15): 1305-1314. DOI: 10.1001/jama.2024.28463.
[16]	Lorenzen S, Götze TO, Thuss-Patience P, et al. Perioperative atezolizumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable esophagogastric cancer: interim results from the randomized, multicenter, phase Ⅱ/Ⅲ DANTE/IKF-s633 trial[J]. J Clin Oncol, 2024, 42(4): 410-420. DOI: 10.1200/JCO.23.00975.
[17]	Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Perioperative durvalumab in gastric and gastroesophageal junction cancer[J]. N Engl J Med, 2025, 393(3): 217-230. DOI: 10.1056/NEJMoa2503701.
[18]	Shitara K, Rha SY, Wyrwicz L, et al. Pembrolizumab plus chemotherapy versus chemotherapy as perioperative therapy in locally advanced gastric and gastroesophageal junction cancer: final analysis of the randomized, phase Ⅲ KEYNOTE-585 study[J]. J Clin Oncol, 2025, 43(29): 3152-3159. DOI: 10.1200/JCO-25-00486.
[19]	Yuan SQ, Nie RC, Jin Y, et al. Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial[J]. Nat Med, 2024, 30(2): 552-559. DOI: 10.1038/s41591-024-02800-6.
[20]	Shao QZ, Deng J, Wu HR, et al. HER2-positive gastric cancer: from targeted therapy to CAR-T cell therapy[J]. Front Immunol, 2025, 16: 1560280. DOI: 10.3389/fimmu.2025.1560280.
[21]	Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial[J]. Lancet, 2023, 402(10418): 2197-2208. DOI: 10.1016/S0140-6736(23)02033-0. pmid: 37871604
[22]	中国抗癌协会胃癌专业委员会. 胃癌抗HER2治疗中国专家共识(2024年版)[J]. 中国肿瘤临床, 2024, 51(23): 1189-1205. DOI: 10.12354/j.issn.1000-8179.2024.20241401.
[23]	Li S, Bao J, Li X, et al. Multicenter phase Ⅰ dose escalation and expansion study of pyrotinib in combination with camrelizumab and chemotherapy as first-line treatment for HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma[J]. EClinical Medicine, 2023, 66: 102314. DOI: 10.1016/j.eclinm.2023.102314.
[24]	Zhou KI, Strickler JH, Chen H. Targeting Claudin-18.2 for cancer therapy: updates from 2024 ASCO annual meeting[J]. J Hematol Oncol, 2024, 17(1): 73. DOI: 10.1186/s13045-024-01595-w.
[25]	Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial[J]. Lancet, 2023, 401(10389): 1655-1668. DOI: 10.1016/S0140-6736(23)00620-7. pmid: 37068504
[26]	Jiang H, Huang M, Wan L, et al. Efficacy and safety of LM-302 (anti-claudin 18.2 ADC) in combination with anti-PD-1 therapy for advanced gastric, gastroesophageal junction cancer and esophageal adenocarcinoma: early-phase study results[J]. J Clin Oncol, 2025, 43(16_suppl): 1039. DOI: 10.1200/JCO.2025.43.16_suppl.4039.
[27]	Smyth EC, Kim KM, Rha SY, et al. FGFR2b protein overexpression: an emerging biomarker in gastric and gastroesophageal junction adenocarcinoma[J]. Cancer Treat Rev, 2025, 139: 102971. DOI: 10.1016/j.ctrv.2025.102971.
[28]	Wainberg ZA, Enzinger PC, Kang YK, et al. Bemarituzumab in patients with FGFR2b-selected gastric or gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double-blind, placebo-controlled, phase 2 study[J]. Lancet Oncol, 2022, 23(11): 1430-1440. DOI: 10.1016/S1470-2045(22)00603-9. pmid: 36244398
[29]	ClinicalTrials.gov. Bemarituzumab plus chemotherapy and nivolumab versus chemotherapy and nivolumab for FGFR2b overexpressed untreated advanced gastric and gastroesophageal junction cancer. (FORTITUDE-102)[EB/OL]. (2021-11-08)[2025-09-10]. https://clinicaltrials.gov/ct2/show/NCT05111626.
[30]	Xu Q, Shao D. Leveraging the synergy between anti-angiogenic therapy and immune checkpoint inhibitors to treat digestive system cancers[J]. Front Immunol, 2024, 15: 1487610. DOI: 10.3389/fimmu.2024.1487610.
[31]	Li C, Tian Y, Zheng Y, et al. Pathologic response of phase Ⅲ study: perioperative camrelizumab plus rivoceranib and chemotherapy versus chemotherapy for locally advanced gastric cancer (DRAGON Ⅳ/CAP 05)[J]. J Clin Oncol, 2025, 43(4): 464-474. DOI: 10.1200/JCO.24.00795.
[32]	Fukuoka S, Hara H, Takahashi N, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ⅰb trial (REGONIVO, EPOC1603)[J]. J Clin Oncol, 2020, 38(18): 2053-2061. DOI: 10.1200/JCO.19.03296. pmid: 32343640
[33]	Kawazoe A, Fukuoka S, Nakamura Y, et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial[J]. Lancet Oncol, 2020, 21(8): 1057-1065. DOI: 10.1016/S1470-2045(20)30271-0. pmid: 32589866
[34]	Zhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications[J]. Cell Mol Immunol, 2020, 17(8): 807-821. DOI: 10.1038/s41423-020-0488-6. pmid: 32612154
[35]	Ji J, Shen L, Li Z, et al. AK104 (PD-1/CTLA-4 bispecific) combined with chemotherapy as first-line therapy for advanced gastric (G) or gastroesophageal junction (GEJ) cancer: updated results from a phase Ⅰb study[J]. J Clin Oncol, 2021, 39(3_suppl): 232. DOI: 10.1200/JCO.2021.39.3_suppl.232.
[36]	André T, Tougeron D, Piessen G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase Ⅱ study[J]. J Clin Oncol, 2023, 41(2): 255-265. DOI: 10.1200/JCO.22.00686.
[37]	Hegewisch-Becker S, Mendez G, Chao J, et al. First-line nivolumab and relatlimab plus chemotherapy for gastric or gastroesophageal junction adenocarcinoma: the phase Ⅱ RELATIVITY-060 study[J]. J Clin Oncol, 2024, 42(17): 2080-2093. DOI: 10.1200/JCO.23.01636.
[38]	Mao C, Xiong A, Qian J, et al. Dual inhibition of LAG-3 and PD-1 with IBI110 and sintilimab in advanced solid tumors: the first-in-human phase Ⅰa/Ⅰb study[J]. J Hematol Oncol, 2024, 17(1): 132. DOI: 10.1186/s13045-024-01651-5.
[39]	Sundstrom EC, Huang X, Wiemer AJ, et al. Anti-TIGIT therapies: a review of preclinical and clinical efficacy and mechanisms[J]. Cancer Immunol Immunother, 2025, 74(8): 272. DOI: 10.1007/s00262-025-04128-7. pmid: 40664804
[40]	Hsu CH, Lu Z, Gao S, et al. Tiragolumab plus atezolizumab and chemotherapy as first-line treatment for patients with unresectable oesophageal squamous cell carcinoma (SKYSCRAPER-08): a randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet Oncol, 2026, 27(1): 103-115. DOI: 10.1016/S1470-2045(25)00401-2.
[41]	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[J]. Clin Cancer Res, 2021, 27(13): 3620-3629. DOI: 10.1158/1078-0432.CCR-20-4746. pmid: 33883177
[42]	Mimura K, Kua LF, Xiao JF, et al. Combined inhibition of PD-1/PD-L1, LAG-3, and TIM-3 axes augments antitumor immunity in gastric cancer-T cell coculture models[J]. Gastric Cancer, 2021, 24(3): 611-623. DOI: 10.1007/s10120-020-01151-8. pmid: 33611641
[43]	Sato H, Okonogi N, Nakano T. Rationale of combination of anti-PD-1/ PD-L1 antibody therapy and radiotherapy for cancer treatment[J]. Int J Clin Oncol, 2020, 25(5): 801-809. DOI: 10.1007/s10147-020-01666-1.
[44]	Zhu M, Chen C, Foster NR, et al. Pembrolizumab in combination with neoadjuvant chemoradiotherapy for patients with resectable adenocarcinoma of the gastroesophageal junction[J]. Clin Cancer Res, 2022, 28(14): 3021-3031. DOI: 10.1158/1078-0432.CCR-22-0413. pmid: 35552651
[45]	Kadota T, Fujii R, Koyama S, et al. A phase Ⅰb study of photo-immunotherapy with ASP-1929 in combination with nivolumab for advanced gastric cancer (GE-PIT, EPOC1901)[J]. Gastric Cancer, 2025, 28(4): 718-724. DOI: 10.1007/s10120-025-01623-9.
[46]	Beck JD, Reidenbach D, Salomon N, et al. mRNA therapeutics in cancer immunotherapy[J]. Mol Cancer, 2021, 20(1): 69. DOI: 10.1186/s12943-021-01348-0. pmid: 33858437
[47]	Lorentzen CL, Haanen JB, Met Ö, et al. Clinical advances and ongoing trials on mRNA vaccines for cancer treatment[J]. Lancet Oncol, 2022, 23(11): e492. DOI: 10.1016/S1470-2045(22)00608-8.
[48]	Nagaoka K, Nakanishi H, Tanaka H, et al. Neoantigen mRNA vaccines induce progenitor-exhausted T cells that support anti-PD-1 therapy in gastric cancer with peritoneal metastasis[J]. Gastric Cancer, 2025, 28(5): 825-836. DOI: 10.1007/s10120-025-01640-8.
[49]	Wang Z, Li N, Feng K, et al. Phase Ⅰ study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors[J]. Cell Mol Immunol, 2021, 18(9): 2188-2198. DOI: 10.1038/s41423-021-00749-x.