Targeting the Epigenetic-Metabolic Axis in the Tumor Microenvironment: How Oncometabolites Reprogram the Molecular Landscape of Cancer?

Abstract

The traditional perspective views cancer as epigenetic disease. However, this review highlights the dynamic interplay between epigenetics and metabolism, where oncometabolites reshape the molecular architecture of the tumor microenvironment (TME). We explore how mutations in tricarboxylic acid (TCA) cycle enzymes (IDH, SDH, FH) or stress-induced metabolic reprogramming lead to the accumulation of metabolites such as D-2-hydroxyglutarate (D2HG), succinate, and fumarate. These oncometabolites act as competitive inhibitors of α-ketoglutarate–dependent dioxygenases, driving DNA hypermethylation, histone modifications, pseudohypoxia, and epitranscriptomic changes such as m6A methylation. Importantly, this crosstalk extends beyond cancer cells, reshaping immune function, promoting T-cell exhaustion via histone lactylation, and influencing ferroptosis. We also discuss emerging therapeutic strategies, including mutant IDH inhibitors, nanomedicine approaches, and AI-driven multi-omics, while acknowledging challenges posed by tumor heterogeneity and metabolic plasticity. Understanding the epigenetic–metabolic axis opens promising avenues for precision and translational oncology.