中国科学院上海营养与健康研究所吕伟研究团队在研究中取得进展。他们报道了CARD11信号调节CD8⁺ T细胞的杀肿瘤功能。相关论文于2025年6月18日发表于国际顶尖学术期刊《自然—免疫学》杂志上。

该课题组人员通过对患者衍生的T细胞受体（TCR）信号蛋白CARD11突变进行主题化，发现信号强度与特克斯细胞分化之间存在负相关。E134G突变体强TCR信号抑制T_ex细胞分化，促进肿瘤生长。相反，K215M突变体减少TCR信号传导，促进T_ex细胞分化，更好地控制肿瘤。这些作用是抑制肿瘤特异性TCR克隆库的T_ex细胞的结果，它减少了免疫病理，但损害了杀肿瘤活性。从机制上讲，CARD11是一种TCR信号强度传感器，通过调节TCR复合物的运输和稳态来控制T_ex细胞的TCR库。通过微调CARD11介导的TCR信号强度，在特克斯细胞分化过程中扩大TCR库，重新激活抗肿瘤功能，并表明了改善癌症免疫治疗的策略。

据介绍，肿瘤微环境中的慢性刺激可诱导具有有限杀瘤活性的CD8⁺ T （T_ex）细胞衰竭。

附：英文原文

Title: CARD11 signaling regulates CD8+ T cell tumoricidal function

Author: Hu, Yu, Zhao, Qifan, Qin, Yingquan, Mei, Song, Wang, Benyu, Zhou, Haoyue, Han, Linli, Zang, Yi, Yao, Liangjiao, He, Zhe, Li, Yingyi, Li, Hecheng, Zhang, Peng, Zhang, Yan, Lenardo, Michael J., Lu, Wei

Issue&Volume: 2025-06-18

Abstract: Chronic stimulation in the tumor microenvironment can induce exhausted CD8+ T (Tex) cells that have limited tumoricidal activity. Here, we show an inverse correlation between signal strength and Tex cell differentiation by using patient-derived mutations in the T cell receptor (TCR)-signaling protein CARD11. Strong TCR signaling of the E134G mutant inhibits Tex cell differentiation and increases tumor growth. Conversely, reduced TCR signaling by the K215M mutant promotes Tex cell differentiation with better tumor control. These effects are a result of a restrained tumor-specific TCR clonal repertoire of Tex cells that reduces immunopathology but compromises tumoricidal activity. Mechanistically, CARD11 is a TCR signal-strength sensor, controlling the TCR repertoire of Tex cells by regulating the trafficking and homeostasis of the TCR complex. Expanding the TCR repertoire during Tex cell differentiation by fine-tuning the CARD11-mediated TCR signal strength reinvigorated antitumor function and indicates a strategy for improving cancer immunotherapy.

DOI: 10.1038/s41590-025-02192-w

Source: https://www.nature.com/articles/s41590-025-02192-w