Glutamine synthetase deficiency enhances CD8 T cell survival and stress resilience in the tumor microenvironment.

ABSTRACT: Cellular immunotherapy has revolutionized the treatment of hematologic malignancies yet has had limited success in the solid tumor microenvironment (TME). While insufficient nutrients can lead to T cell metabolic stress in the TME, the glutamine antagonist DON can paradoxically enhance antitumor immunity. Because DON inhibits both essential and nonessential enzymes whose impairment may contribute to dose-limiting toxicities, mechanisms underlying DON-induced antitumor activity have remained unclear. Here, we aimed to identify specific DON targets that increase T cell antitumor activity and test if more selective inhibition of glutamine metabolism could replicate the effects of DON with reduced toxicity. CRISPR screening in the TME of DON-relevant glutamine metabolizing enzymes identified s

SUBMITTER: Fisher-Gupta EL 

PROVIDER: S-EPMC12856555 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature