Oncometabolite D-2HG alters T cell metabolism to impair CD8+ T cell function

Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d-2-hydroxyglutarate (D-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell–intrinsic effects of D-2HG are well understood, but its tumor cell–nonautonomous roles remain poorly explored. We compared the oncometabolite D-2HG with its enantiomer, L-2HG, and found that tumor-derived D-2HG was taken up by CD8⁺ T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of D-2HG. D-2HG and inhibition of LDH drive a metabolic program and immune CD8⁺ T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.