Liu Yi, Ni Haochen, Li Jie, Yang Jing, Sekielyk Ivann, Snow Bryan E, Zhang Zihao, Zhang Feifan, Paul Michael St, Han Jinyi, Kates Meghan, Liu Shaofeng, Zhang Yawei, Huang Zurui, Xu Yin, Saibil Samuel D, Mak Tak W, Han Dali, Xu Meng Michelle
Institute for Immunology, Tsinghua University, Beijing, China.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Nat Immunol. 2025 Jul 22. doi: 10.1038/s41590-025-02232-5.
Adoptive T cell therapies have therapeutic potential for treating solid tumors, but long-term efficacy is limited by reduced functional fitness and poor persistence within the tumor microenvironment. Here we show that intratumoral T cells undergo translatome remodeling, transitioning into a hypertranslational state as they acquire dysfunctional traits. The RNA-binding protein LARP4 is a translation regulator that drives hypertranslation and dysfunction by selectively enhancing the translation of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs in exhausted T cells, disrupting OXPHOS subunit balance and causing mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8 T cells reduces hypertranslation, restores mitochondrial function, mitigates exhaustion and enhances effector persistence, resulting in enhanced anti-tumor responses. Additionally, LARP4 knockdown in chimeric antigen receptor T cells prevents terminal exhaustion and improves the response to liquid and solid tumors. This study highlights translation dysregulation as a determinant of T cell dysfunction in tumors.
过继性T细胞疗法在治疗实体瘤方面具有治疗潜力，但长期疗效受到肿瘤微环境中功能适应性降低和持久性差的限制。我们在此表明，肿瘤内T细胞会经历翻译组重塑，在获得功能失调特征时转变为超翻译状态。RNA结合蛋白LARP4是一种翻译调节因子，通过选择性增强耗竭T细胞中核编码的氧化磷酸化（OXPHOS）mRNA的翻译来驱动超翻译和功能失调，破坏OXPHOS亚基平衡并导致线粒体功能障碍。在肿瘤特异性CD8 T细胞中敲除Larp4可减少超翻译，恢复线粒体功能，减轻耗竭并增强效应细胞持久性，从而增强抗肿瘤反应。此外，嵌合抗原受体T细胞中LARP4的敲低可防止终末耗竭并改善对液体和实体瘤的反应。这项研究强调翻译失调是肿瘤中T细胞功能障碍的一个决定因素。
