Gene

Molecular biology

Isocitrate dehydrogenase

Biology

Glycolysis

T cell

Metabolism

Cancer research

Biochemistry

Immunology

Lactate dehydrogenase

Immune system

In vitro

Enzyme

Cytotoxic T cell

Chemistry

Cell

Carcinogenesis

Science

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.

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

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

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