Fig. 2.

The tumor-promoting effects of oncometabolites. a The classical oncometabolites (fumarate, succinate, D-2-hydroxyglutarate — 2HG) and their epigenetic and angiogenic effects are shown in the figure. The accumulation of these oncometabolites inhibit prolyl hydroxylases and stabilize HIF1α (causing hypoxia), and they have a direct regulatory role by competitively inhibiting dioxygenases, influencing promoter methylation — activation/inactivation of oncogenes and tumor suppressor genes, respectively. b Lactate (as an oncometabolite) causes an acidic microenvironment, which aids tumor progression. Tumor and stromal cells produce lactate in correlation with blood vessel distance and tumorigenic alterations (e.g., oncogene-driven pseudohypoxia). Lactate and decreased pH have many tumor promoter functions: inhibition of antitumor immune effector cells, induction of therapy resistance, and sourcing of alternative nutrient supply for highly oxygenated normal and malignant cells. The acidic microenvironment also causes cancer-associated fibroblasts (CAFs) to produce growth factors, cytokines, feed tumor cells (TCA replenishing metabolites and the use of amino acids as nutrients), and matrix degradation. Additionally, the low pH could play a role in cytokine and enzyme activation, assisting with tumor cell adaptation, matrix remodeling, and tumor cell migration, as part of immunosuppressive and tumor-promoting niches. c The names, sources, metabolic contributions, and the relevance of traditional and non-traditional oncometabolites in various cancers