实体瘤CAR-T治疗的临床突破与工程化优化：从CLDN18.2胃癌到肿瘤微环境重塑的研究 进展

Clinical Breakthroughs and Engineering Optimization of CAR-T Cell Therapy for Solid Tumors: Advances from CLDN18.2-Targeted Therapy in Gastric Cancer to Tumor Microenvironment Remodeling

摘要: 嵌合抗原受体T细胞疗法(chimeric antigen receptor T-cell therapy, CAR-T)已在复发/难治性B细胞恶性肿瘤和多发性骨髓瘤中取得突破性疗效，并推动肿瘤治疗进入“活细胞药物”时代。然而，与血液系统肿瘤相比，CAR-T在实体瘤中的临床转化一直较为艰难。实体瘤并不是一团简单的肿瘤细胞，而是由肿瘤细胞、基质细胞、异常血管、免疫抑制细胞、代谢产物和细胞因子共同构成的复杂生态系统。抗原异质性、T细胞浸润不足、肿瘤微环境免疫抑制、细胞耗竭、实体瘤屏障以及on-target/off-tumor毒性，是限制实体瘤CAR-T疗效的核心因素。近年，CLDN18.2靶向CAR-T在晚期胃癌/胃食管结合部癌中取得随机对照II期阳性结果，成为实体瘤CAR-T领域的重要临床突破。同时，GD2、B7-H3、EGFRvIII、IL13Rα2、GPC3、MSLN、HER2等靶点研究不断推进，局部递送、双靶点/多靶点CAR-T、逻辑门控CAR-T、装甲CAR-T、通用型CAR-T和体内生成CAR-T等工程化策略也正在改写该领域的发展路径。本文围绕实体瘤CAR-T治疗的临床突破、靶点布局、治疗障碍、工程化优化和未来转化方向进行综述，以期为实体瘤细胞治疗研究提供参考。

Abstract: Chimeric antigen receptor T-cell therapy (CAR-T) has achieved breakthrough efficacy in relapsed or refractory B-cell malignancies and multiple myeloma, marking the advent of the “living drug” era in cancer treatment. However, compared with hematological malignancies, the clinical translation of CAR-T therapy in solid tumors remains challenging. Solid tumors are not simply aggregates of malignant cells, but rather complex ecosystems composed of tumor cells, stromal cells, abnormal vasculature, immunosuppressive cells, metabolites, and cytokines. Antigen heterogeneity, insufficient T-cell infiltration, immunosuppressive tumor microenvironment, T-cell exhaustion, physical barriers within solid tumors, and on-target/off-tumor toxicity are key factors limiting the therapeutic efficacy of CAR-T cells in solid tumors. In recent years, CLDN18.2-targeted CAR-T therapy has demonstrated positive results in a randomized phase II trial for advanced gastric or gastroesophageal junction cancer, representing an important clinical breakthrough in the field of solid tumor CAR-T therapy. Meanwhile, increasing progress has been made in CAR-T strategies targeting GD2, B7-H3, EGFRvIII, IL13Rα2, GPC3, MSLN, HER2, and other tumor-associated antigens. In parallel, engineering strategies such as locoregional delivery, dual- or multi-targeted CAR-T cells, logic-gated CAR-T cells, armored CAR-T cells, universal CAR-T cells, and in vivo-generated CAR-T cells are reshaping the developmental landscape of this field. This review summarizes recent clinical breakthroughs, target selection, therapeutic barriers, engineering optimization strategies, and future translational directions of CAR-T therapy for solid tumors, with the aim of providing a reference for further research and clinical development of cellular immunotherapy in solid tumors.