Oncometabolites in Cancer Metabolism: Mechanistic Insights and Biomarker Potential- A Narrative Review

Cancer cells undergo adaptation in hostile tumor microenvironments and go through extensive metabolic reprogramming for flourishing. Oncogenic transformation caused by mutations in some metabolic enzymes results in the generation of some metabolic intermediates called onco-metabolites. A growing body of evidence highlights the role of oncometabolites such as 2-hydroxyglutarate (2-HG), fumarate, and succinate in driving oncogenesis through epigenetic remodeling, altered redox balance, and interrupted cellular signaling. These metabolites are usually accumulated due to mutation in major metabolic enzymes, including Isocitrate Dehydrogenase 1 and 2 (IDH1/2), Succinate Dehydrogenase (SDH), and Fumarate Hydratase (FH), and serve as competitive inhibitors of α-ketoglutarate-dependent dioxygenases, thereby affecting DNA and histone demethylation. This review widely synthesizes the origin, biochemical functions, and oncogenic implications of oncometabolites, emphasizing their potential utility as diagnostic and prognostic biomarkers through liquid biopsy and metabolomic profiling.

We conducted a focused literature search of PubMed and Google Scholar for articles up to 2025, focusing on oncometabolites and their carcinogenic role, molecular mechanisms, biomarker potentials, and therapeutic targeting.

Mutant IDH enzymes produce (R)-2-HG, while loss of SDH or FH activity leads to succinate and fumarate accumulation. These oncometabolites inhibit α-KG-dependent dioxygenases-including TET and JmjC families and prolyl hydroxylases resulting in DNA/histone hypermethylation, pseudohypoxia, altered redox homeostasis, and protein succination. Clinically, 2-HG and other metabolic signatures are detectable by magnetic resonance spectroscopy and mass spectrometry-based metabolomics, and metabolic profiling shows promise for diagnosis, prognosis, and monitoring. Therapeutic strategies in development focus on direct enzyme inhibition, metabolic modulation, and combinations with immunotherapy; however, tumor heterogeneity and assay sensitivity remain major obstacles.

Altogether, this review highlights how onco-metabolites are connected to cancer biology and how it will impact future precision oncology.