Illuminating the cross-talk between tumor metabolism and immunity in IDH-mutated cancers

Mutations in the genes encoding isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are key drivers of diverse cancers, including gliomas and hematological malignancies. IDH mutations cause neomorphic enzymatic activity that results in the production of the oncometabolite 2-hydroxyglutarate (2-HG). In addition to 2-HG’s well-known effects on tumor cells themselves, it has become increasingly clear that 2-HG directly influences the tumor microenvironment (TME). In particular, the non-cell-autonomous impact of 2-HG on the immune system likely plays a major role in shaping disease development and response to therapy. It is therefore critical to understand how IDH mutations affect the metabolism, epigenetics, and functions of tumor-infiltrating immune cells. Such knowledge may point towards new therapeutic approaches to treat IDH-mutant cancers.