Stress-Mediated Attenuation of Translation Undermines T-cell Activity in Cancer

Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvi-ronment (TME) may impact protein translation in T cells and antitumor immunity. Using human and mouse tumors, we demonstrated here that protein translation in T cells is repressed in solid tumors. Reduced glucose availability to T cells in the TME led to activation of the unfolded protein response (UPR) element eIF2a (eukaryotic translation initiation factor 2 alpha). Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2a undermines the ability of T cells to suppress tumor growth. Reprograming T-cell metabolism was able to alleviate p-eIF2a accumulation and translational atten-uation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that protea-some activity mitigates induction of p-eIF2a to support optimal antitumor T-cell function, protecting from translation attenua-tion and enabling prolonged cytokine synthesis in solid tumors. Together, these data identify a new therapeutic avenue to fuel the efficacy of tumor immunotherapy. Significance: Proteasome function is a necessary cellular component for endowing T cells with tumor killing capacity by mitigating translation attenuation resulting from the unfold -ed protein response induced by stress in the tumor micro -environment.