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

Brian P. Riesenberg, Elizabeth G. Hunt, Megan D. Tennant, Katie E. Hurst, Alex M. Andrews, Lee R. Leddy, David M. Neskey, Elizabeth G. Hill, Guillermo O.Rangel Rivera, Chrystal M. Paulos, Peng Gao, Jessica E. Thaxton*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)4386-4399
Number of pages14
JournalCancer Research
Issue number23
StatePublished - Dec 1 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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