CAR-T细胞治疗胃癌:从靶点探索到临床转化的突破与挑战

CAR-T cell therapy for gastric cancer: advances and challenges from target discovery to clinical translation

  • 摘要: 胃癌是全球高发的恶性肿瘤,治疗手段有限。嵌合抗原受体T细胞(chimeric antigen receptor T-cell,CAR-T)疗法为胃癌治疗带来新希望,但其应用仍面临诸多挑战。本文旨在综述CAR-T细胞治疗胃癌的最新进展,系统阐述其从靶点探索到临床转化的关键突破与核心挑战,并展望未来发展方向。本文讨论了理想靶点的筛选标准,并重点评述了主流靶点的研究现状,包括已证实显著疗效的Claudin-18.2(CLDN18.2)以及面临不同挑战的HER-2、CEA、EpCAM和MUC1等。本文亦深入剖析了制约CAR-T疗效的三大核心障碍及其应对策略:通过局部递送、武装型CAR-T及联合治疗等方式攻克免疫抑制性肿瘤微环境(tumor microenvironment,TME);利用亲和力调控及逻辑门设计等工程化改造规避中靶脱瘤毒性(on-target/ off-tumor toxicity,OTOT);采用早期单采、快速制备平台及通用型CAR-T等策略优化生产流程、降低成本。未来多维度、整合性的创新策略是推动CAR-T疗法在实体瘤领域取得全面突破的关键。

     

    Abstract: Gastric cancer is a malignant tumor with high prevalence worldwide and limited therapeutic options. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising approach for gastric cancer treatment; however, its application faces substantial challenges. This review provides comprehensive summary of the recent advances in CAR-T cell therapy for gastric cancer, systematic analysis of critical break throughs and core challenges from target discovery to clinical translation, and outlining of future perspectives. We describe the criteria for ideal target selection and highlight the current research landscape of major targets, including CLDN18.2 that demonstrated efficacy, and targets facing distinct challenges, including HER-2, CEA, EpCAM, and MUC1. This review also finely dissects three central barriers restricting CAR-T cell efficacy, and discusses corresponding countermeasures: overcoming the immunosuppressive tumor microenvironment through strategies such as local delivery, armored CAR-T cells, and combination therapies; engineering approaches including affinity modulation and logic-gate designs to mitigate on-target/off-tumor toxicity; and optimization of manufacturing processes and reduction of costs via early leukapheresis, rapid production platforms, and universal CAR-T cell strategies. Future multidimensional, integrative, and innovative strategies are pivotal for achieving comprehensive break throughs in CAR-T cell therapy for solid tumors.

     

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