Fig. 2.

The impact of 2-HG on the adaptive immune system within TIME. D-2-HG generally contributes to the "cold tumor" characteristic by interfering with the proliferation and differentiation of CD8⁺ T cells. This interference occurs through the inhibition of Ca2+-dependent NFAT-mediated T cell activation, TET1/2-mediated DNA methylation, HIF-1α, LDHA, and the orchestration of glucose metabolism towards OXPHOS. Consequently, the cytotoxic effect and immune memory of CD8⁺ T cells are impaired. CD4⁺ T cells are also inhibited, resulting in a higher population of T_Reg cells and fewer effective cytokines released from mature CD4⁺ cells. In contrast, L-2-HG induces an immune-infiltrated status by upregulating the proliferation and differentiation of effector and memory T cells. 2-HG: 2-hydroxyglutarate; TIME: tumor immune microenvironment; TET: ten-eleven translocation; HIF: hypoxia-inducible factors; LDHA: lactate dehydrogenase A; OXPHOS: oxidative phosphorylation; T_Reg: regulatory T lymphocytes; STAT1: Signal transducer and activator of transcription 1.