LARP4-mediated hypertranslation drives T cell dysfunction in tumors.

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.