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用MMP2工程的CAR-T细胞克服固体瘤中的 stromal 抵抗

Jiaxin Tu¹, Yuge Zhu², Xinyu Li¹

¹Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Biochemistry and Molecular Biology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.

Pharmacological research

|March 16, 2026

概括

矩阵金属蛋白酶-2 (MMP2) 通过降解细胞外矩阵屏障,增强了固体瘤的仿真抗原受体 (CAR) T 细胞疗法. 这种单酶方法改善了T细胞透和抗瘤功效,提供了一个可扩展的策略.

科学领域:

免疫治疗是一种免疫疗法.
在瘤学瘤学.
生物化学生物化学

背景情况:

化学抗原受体 (CAR) T细胞疗法在固体瘤中面临挑战,原因是细胞外矩阵 (ECM) 结构障碍.
以前使用多基矩阵金属蛋白酶 (MMPs) 的策略增加了复杂性,而单个MMP7过度表达的疗效有限.

研究的目的:

确定一种单一的酶,用于有效的ECM重塑,以增强固体瘤中CAR T细胞疗法.
评估矩阵金属蛋白酶-2 (MMP2) 在克服ECM介导抗性的疗效.

主要方法:

改造CAR T细胞 (准美索林和B7H3) 以共同表达MMP2.2.
在体外评估ECM穿越,T细胞适应性和细胞毒性.
在癌症相关纤维细胞 (CAF) 丰富异种移植模型中的体内评估.

主要成果:

通过促进ECM穿越,MMP2共同表达增强了CAR T细胞透和细胞毒性.
通过使用泛MMP抑制剂GM6001.1的抑制来证实MMP2的作用.
经MMP2工程的CAR T细胞在体内显示了内积增加和持久的瘤控制.

结论:

矩阵金属蛋白酶-2 (MMP2) 是用于固体瘤ECM重塑的强有力的单个酶.
基于MMP2的策略提供了一种简单,可扩展和临床可转换的方法,用于在CAR T细胞治疗中克服 stromal 抵抗.

关键词:

在CAR-T细胞中.细胞外矩阵重塑细胞外矩阵重塑矩阵金属蛋白酶2 (MMP2) 的作用.

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