Oncometabolite <scp>d</scp> -2HG alters T cell metabolism to impair CD8 ⁺ T cell function

TLDR

Gain‑of‑function IDH mutations produce the oncometabolite d‑2HG, which drives tumorigenesis epigenetically, yet its effects on non‑tumor cells remain largely unexplored. Tumor‑derived d‑2HG is absorbed by CD8⁺ T cells, where it targets LDH, reprograms metabolism, reduces cytotoxicity and interferon‑γ signaling, and this dysfunction is observed in IDH1‑mutant glioma patients.

Abstract

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.