Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1⁺ progenitor CD8⁺ T cells to improve immunotherapy.

ABSTRACT: TCF1^high progenitor CD8⁺ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1^high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2^KO CD8⁺ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-¹³C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8⁺ T cells

SUBMITTER: Markowitz GJ 

PROVIDER: S-EPMC12636053 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature