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

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 toward a TCF1^high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8⁺ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.