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

TCF1^high progenitor CD8+ T cells mediate the efficacy of PD-1 blockade, 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 central memory-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 towards a TCF1^high population, generated a unique transcriptional landscape, 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 amenable to checkpoint blockade.