晚期非小细胞肺癌抗PD-1/PD-L1治疗耐药机制的研究进展

doi:10.3760/cma.j.cn371439-20250319-00008

摘要/Abstract

摘要：

尽管基于抗程序性死亡受体1（PD-1）及其配体（PD-L1）的免疫检查点抑制剂治疗可显著改善晚期非小细胞肺癌患者的生存预后，但原发性和继发性耐药导致部分人群获益有限。抗PD-1/PD-L1治疗的耐药机制尤为复杂，且受多种因素影响。系统梳理PD-1/PD-L1免疫检查点抑制剂耐药机制的最新研究成果，可为优化非小细胞肺癌患者的治疗策略提供科学依据。

关键词: 癌，非小细胞肺, 免疫检查点抑制剂, 肿瘤微环境, 抗药性，肿瘤

Abstract:

Although immune checkpoint inhibitor therapy based on anti-programmed death-1 （PD-1） and programmed death-ligand 1 （PD-L1） can significantly improve the survival prognosis of patients with advanced non-small cell lung cancer， primary and secondary drug resistance result in limited benefits for some individuals. The resistance mechanism of anti-PD-1/PD-L1 therapy is particularly complex and is influenced by multiple factors. A systematic review of the latest research results on the resistance mechanism to PD-1/PD-L1 immune checkpoint inhibitors can provide scientific basis for optimizing the treatment strategy of non-small cell lung cancer patients.

Key words: Carcinoma， non-small-cell lung, Immune checkpoint inhibitors, Tumor microenvironment, Drug resistance，neoplasm

李婷, 周琦, 张倩, 陈洁. 晚期非小细胞肺癌抗PD-1/PD-L1治疗耐药机制的研究进展[J]. 国际肿瘤学杂志, 2026, 53(1): 57-61.

Li Ting, Zhou Qi, Zhang Qian, Chen Jie. Research progress on resistance mechanisms of anti-PD-1/PD-L1 therapy in advanced non-small cell lung cancer[J]. Journal of International Oncology, 2026, 53(1): 57-61.

参考文献 37

[1]	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263. DOI: 10.3322/caac.21834.
[2]	刘超星, 严雪冰, 杨梦雪, 等. 非小细胞肺癌免疫治疗的临床影响因素[J]. 国际肿瘤学杂志, 2021, 48(12): 751-754. DOI: 10.3760/cma.j.cn371439-20210927-00149.
[3]	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)非小细胞肺癌诊疗指南2024[M]. 北京: 人民卫生出版社, 2024.
[4]	National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®): Non-Small Cell Lung Cancer. Version 4.2024[EB/OL]. (2024-04-01) [2025-03-01]. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450.
[5]	中国临床肿瘤学会非小细胞肺癌专业委员会. 驱动基因阴性晚期非小细胞肺癌一线免疫治疗耐药评估及治疗策略中国专家共识(2024版)[J]. 中华医学杂志, 2024, 104(6): 411-426. DOI: 10.3760/cma.j.cn112137-20230927-00589.
[6]	王洁, 赫捷, 国家肿瘤质控中心肺癌质控专家委员会, 等. 中国肺癌免疫治疗规范化应用指南(2024版)[J]. 中国肿瘤临床与康复, 2024, 31(11): 659-700. DOI: 10.13455/j.cnki.cjcor.113494-2024-2024-0207.
[7]	Vesely MD, Zhang T, Chen L. Resistance mechanisms to anti-PD cancer immunotherapy[J]. Annu Rev Immunol, 2022, 40: 45-74. DOI: 10.1146/annurev-immunol-070621-030155. pmid: 35471840
[8]	Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score≥50[J]. J Clin Oncol, 2021, 39(21): 2339-2349. DOI: 10.1200/JCO.21.00174.
[9]	Liu YT, Sun ZJ. Turning cold tumors into hot tumors by improving T-cell infiltration[J]. Theranostics, 2021, 11(11): 5365-5386. DOI: 10.7150/thno.58390.
[10]	谢红霞, 左金辉, 廖冬颖, 等. PD-L1抑制剂在非小细胞肺癌中的应用[J]. 国际肿瘤学杂志, 2022, 49(2): 111-115. DOI: 10.3760/cma.j.cn371439-20210121-00018.
[11]	Oguri T, Sasada S, Seki S, et al. A case of hyperprogressive disease following atezolizumab therapy for pulmonary pleomorphic carcinoma with epidermal growth factor receptor mutation[J]. Respir Med Case Rep, 2021, 33: 101405. DOI: 10.1016/j.rmcr.2021.101405.
[12]	To KKW, Fong W, Cho WCS. Immunotherapy in treating EGFR-mutant lung cancer: current challenges and new strategies[J]. Front Oncol, 2021, 11: 635007. DOI: 10.3389/fonc.2021.635007.
[13]	Tian T, Li Y, Li J, et al. Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: a multicenter real-world analysis[J]. Transl Lung Cancer Res, 2024, 13(4): 861-874. DOI: 10.21037/tlcr-24-116.
[14]	Zavitsanou AM, Pillai R, Hao Y, et al. KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance[J]. Cell Rep, 2023, 42(11): 113295. DOI: 10.1016/j.celrep.2023.113295.
[15]	Gao G, Liao W, Ma Q, et al. KRAS G12D mutation predicts lower TMB and drives immune suppression in lung adenocarcinoma[J]. Lung Cancer, 2020, 149: 41-45. DOI: 10.1016/j.lungcan.2020.09.004. pmid: 32956987
[16]	Mortezaee K, Majidpoor J. Mechanisms of CD8⁺ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1[J]. Biomed Pharmacother, 2023, 163: 114824. DOI: 10.1016/j.biopha.2023.114824.
[17]	Budimir N, Thomas GD, Dolina JS, et al. Reversing T-cell exhaustion in cancer: lessons learned from PD-1/PD-L1 immune checkpoint blockade[J]. Cancer Immunol Res, 2022, 10(2): 146-153. DOI: 10.1158/2326-6066.CIR-21-0515.
[18]	Younis M, Wu Y, Fang Q, et al. Synergistic therapeutic antitumor effect of PD-1 blockade cellular vesicles in combination with iguratimod and rhodium nanoparticles[J]. J Colloid Interface Sci, 2023, 649: 929-942. DOI: 10.1016/j.jcis.2023.06.030.
[19]	Larroquette M, Guegan JP, Besse B, et al. Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies[J]. J Immunother Cancer, 2022, 10(5): e003890. DOI: 10.1136/jitc-2021-003890.
[20]	La Fleur L, Botling J, He F, et al. Targeting MARCO and IL37R on immunosuppressive macrophages in lung cancer blocks regulatory T cells and supports cytotoxic lymphocyte function[J]. Cancer Res, 2021, 81(4): 956-967. DOI: 10.1158/0008-5472.CAN-20-1885. pmid: 33293426
[21]	Huang Z, Xiao Z, Yu L, et al. Tumor-associated macrophages in non-small-cell lung cancer: from treatment resistance mechanisms to therapeutic targets[J]. Crit Rev Oncol Hematol, 2024, 196: 104284. DOI: 10.1016/j.critrevonc.2024.104284.
[22]	Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy[J]. Nat Rev Clin Oncol, 2021, 18(1): 9-34. DOI: 10.1038/s41571-020-0403-1.
[23]	Cheng B, Ding K, Chen P, et al. Anti-PD-L1/TGF-βR fusion protein (SHR-1701) overcomes disrupted lymphocyte recovery-induced resistance to PD-1/PD-L1 inhibitors in lung cancer[J]. Cancer Commun (Lond), 2022, 42(1): 17-36. DOI: 10.1002/cac2.12244.
[24]	Li X, Yang Y, Zhang B, et al. Lactate metabolism in human health and disease[J]. Signal Transduct Target Ther, 2022, 7(1): 305. DOI: 10.1038/s41392-022-01151-3.
[25]	Liberti MV, Locasale JW. The warburg effect: how does it benefit cancer cells?[J]. Trends Biochem Sci, 2016, 41(3): 211-218. DOI: 10.1016/j.tibs.2015.12.001. pmid: 26778478
[26]	Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor micro-environments[J]. Cancer Cell, 2022, 40(2): 201-218.e9. DOI: 10.1016/j.ccell.2022.01.001.
[27]	De Martino M, Rathmell JC, Galluzzi L, et al. Cancer cell metabolism and antitumour immunity[J]. Nat Rev Immunol, 2024, 24(9): 654-669. DOI: 10.1038/s41577-024-01026-4. pmid: 38649722
[28]	Chen Y, Zhou Y, Ren R, et al. Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma[J]. J Immunother Cancer, 2024, 12(7): e008811. DOI: 10.1136/jitc-2024-008811.
[29]	Xiao C, Xiong W, Xu Y, et al. Immunometabolism: a new dimension in immunotherapy resistance[J]. Front Med, 2023, 17(4): 585-616. DOI: 10.1007/s11684-023-1012-z.
[30]	Mitchell TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase Ⅰ results from a multicenter, open-label phase Ⅰ/Ⅱ trial (ECHO-202/KEYNOTE-037)[J]. J Clin Oncol, 2018, 36(32): 3223-3230. DOI: 10.1200/JCO.2018.78.9602. pmid: 30265610
[31]	Kotecki N, Vuagnat P, O'Neil BH, et al. A phase Ⅰ study of an IDO-1 inhibitor (LY3381916) as monotherapy and in combination with an anti-PD-L1 antibody (LY3300054) in patients with advanced cancer[J]. J Immunother, 2021, 44(7): 264-275. DOI: 10.1097/CJI.0000000000000368. pmid: 33928928
[32]	Derosa L, Routy B, Thomas AM, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer[J]. Nat Med, 2022, 28(2): 315-324. DOI: 10.1038/s41591-021-01655-5. pmid: 35115705
[33]	Jiang SS, Xie YL, Xiao XY, et al. Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer[J]. Cell Host Microbe, 2023, 31(5): 781-797.e9. DOI: 10.1016/j.chom.2023.04.010.
[34]	Park JS, Gazzaniga FS, Wu M, et al. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance[J]. Nature, 2023, 617(7960): 377-385. DOI: 10.1038/s41586-023-06026-3.
[35]	Lam KC, Araya RE, Huang A, et al. Microbiota triggers STING-type Ⅰ IFN-dependent monocyte reprogramming of the tumor microenvironment[J]. Cell, 2021, 184(21): 5338-5356.e21. DOI: 10.1016/j.cell.2021.09.019.
[36]	Zhu Z, Cai J, Hou W, et al. Microbiome and spatially resolved metabolomics analysis reveal the anticancer role of gut Akkermansia muciniphila by crosstalk with intratumoral microbiota and reprogramming tumoral metabolism in mice[J]. Gut Microbes, 2023, 15(1): 2166700. DOI: 10.1080/19490976.2023.2166700.
[37]	Preet R, Islam MA, Shim J, et al. Gut commensal bifidobacterium-derived extracellular vesicles modulate the therapeutic effects of anti-PD-1 in lung cancer[J]. Nat Commun, 2025, 16(1): 3500. DOI: 10.1038/s41467-025-58553-4.