清华大学徐萌小组取得一项新突破。他们的研究开发出了larp4介导的超翻译驱动肿瘤中的T细胞功能障碍。2025年7月22日出版的《自然—免疫学》杂志发表了这项成果。

这里研究组展示了肿瘤内的T当细胞获得功能失调的特性时，它们会经历翻译体重塑，过渡到超翻译状态。RNA结合蛋白LARP4是一种翻译调节因子，通过选择性地增强衰竭T破坏OXPHOS亚基平衡并引导线粒体功能障碍。在肿瘤特异性CD8⁺ T中敲除Larp4细胞减少超翻译，恢复线粒体功能，减轻疲劳，增强效应持久性，从而增强抗肿瘤反应。此外，嵌合抗原受体T细胞防止末期衰竭，提高对液体和实体肿瘤的反应。本研究强调翻译失调是T肿瘤中的细胞功能障碍。

据了解，收养T细胞疗法具有治疗实体瘤的潜力，但长期疗效受到功能适应度降低和肿瘤微环境内持久性差的限制。

附：英文原文

Title: LARP4-mediated hypertranslation drives T cell dysfunction in tumors

Author: 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

Issue&Volume: 2025-07-22

Abstract: Adoptive Tcell 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 Tcells 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 Tcells, disrupting OXPHOS subunit balance and causing mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8+ Tcells reduces hypertranslation, restores mitochondrial function, mitigates exhaustion and enhances effector persistence, resulting in enhanced anti-tumor responses. Additionally, LARP4 knockdown in chimeric antigen receptor Tcells prevents terminal exhaustion and improves the response to liquid and solid tumors. This study highlights translation dysregulation as a determinant of Tcell dysfunction in tumors.

DOI: 10.1038/s41590-025-02232-5

Source: https://www.nature.com/articles/s41590-025-02232-5