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Metabolic and epigenetic reprogramming are fundamental hallmarks of cancer, enabling tumor cells to adapt to hostile environments, evade immune surveillance, and sustain uncontrolled proliferation. Mutations in metabolic enzymes, such as isocitrate dehydrogenase 1 (IDH1), drive profound changes in cellular physiology by producing oncometabolites that disrupt α-KG–dependent processes. The mutant IDH1 enzyme (mIDH1) generates (R)-2-hydroxyglutarate (2HG), which alters the epigenetic landscape by inhibiting histone and DNA demethylases, ultimately silencing tumor suppressive pathways and immune signaling. These alterations contribute to immune escape by suppressing innate immune activation. 2HG-driven hypermethylation of cGAS silences the cGAS-STING pathway, preventing cytosolic DNA sensing and maintaining an immunologically “cold” tumor microenvironment. Inhibition of mIDH1 reverses these effects by restoring cGAS expression, reactivating transposable elements, and triggering viral mimicry. This leads to CD8+ T cell infiltration and IFN-γ-driven tumor suppression, with TET2-mediated chromatin remodeling playing a crucial role in the IFN-γ response. Beyond tumor-intrinsic effects, 2HG may influence immune cells, endothelial cells, and fibroblasts, further shaping the tumor microenvironment. Emerging evidence suggests that 2HG regulates protein post-translational modifications, expanding its functional impact. Additionally, CRISPR-based screening has identified novel vulnerabilities in IDH1-mutant tumors, highlighting new therapeutic opportunities to counteract immune suppression and improve treatment outcomes.