LARP4-mediated translation remodeling drives T cell exhaustion in tumor (PRJCA030194)

Using low-input ribosome sequencing (RPLace-seq), we uncover that intratumoral T cells undergo translatome remodeling and shift into a hyper-translation state as they acquire dysfunctional and exhaustion traits. We identify the RNA-binding protein LARP4 as a translation regulator mediating this hypertranslation state in exhausted T cells within tumors. LARP4 directly recognizes and increases the translation efficiency of a group of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs in exhausted T cells while not affecting that of mitochondria-encoded mRNAs, thereby leading to an imbalance in OXPHOS subunits synthesis and mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8+ T cells attenuates hyper-translation of intratumor T cells, restores their mitochondrial fitness, and enhances effector T cell differentiation with improved persistence within tumors, ultimately resulting in a superior antitumor response. Moreover, LARP4 knockdown in chimeric antigen receptor (CAR) T cells prevents terminal exhaustion differentiation of CAR T cells and improves their anti-tumor potency in both leukemia and solid tumors. Our study unveils the involvement of translation regulation in fine-tuning T cell fitness within tumors and identifies LARP4 as a potential target for enhancing the effectiveness of adoptive T cell therapies against solid tumors.