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

Cancer Res. 2022 Dec 2;82(23):4386-4399. doi: 10.1158/0008-5472.CAN-22-1744.


Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (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 eIF2α (eukaryotic translation initiation factor 2 alpha). Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2α undermines the ability of T cells to suppress tumor growth. Reprograming T-cell metabolism was able to alleviate p-eIF2α accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2α to support optimal antitumor T-cell function, protecting from translation attenuation 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 unfolded protein response induced by stress in the tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism
  • Humans
  • Immunotherapy / methods
  • Mice
  • Neoplasms* / therapy
  • Proteasome Endopeptidase Complex
  • T-Lymphocytes* / metabolism
  • Tumor Microenvironment


  • Proteasome Endopeptidase Complex
  • Eukaryotic Initiation Factor-2