TCA cycle-derived oncometabolites in cancer and the immune microenvironment

Abstract

Oncometabolites are aberrant metabolic byproducts that arise from mutations in enzymes of the tricarboxylic acid (TCA) cycle or related metabolic pathways and play central roles in tumor progression and immune evasion. Among these, 2-hydroxyglutarate (2-HG), succinate, and fumarate are the most well-characterized, acting as competitive inhibitors of α-ketoglutarate-dependent dioxygenases to alter DNA and histone methylation, cellular differentiation, and hypoxia signaling. More recently, itaconate, an immunometabolite predominantly produced by activated macrophages, has been recognized for its dual roles in modulating inflammation and tumor immunity. These metabolites influence cancer development through multiple mechanisms, including epigenetic reprogramming, redox imbalance, and post-translational protein modifications. Importantly, their effects are not limited to cancer cells but extend to various components of the tumor microenvironment, such as T cells, macrophages, dendritic cells, and endothelial cells, reshaping immune responses and contributing to immune suppression. In this review, we highlight the emerging insights into the roles of TCA cycle-associated oncometabolites in cancer biology and immune regulation. We discuss how these metabolites impact both tumor-intrinsic processes and intercellular signaling within the tumor microenvironment. Finally, we examine therapeutic strategies targeting oncometabolite pathways, including mutant IDH inhibitors, α-ketoglutarate mimetics, and immunometabolic interventions, with the goal of restoring immune surveillance and improving cancer treatment outcomes.

Keywords: 2-hydroxyglutarate; Epigenetic regulation; Fumarate; Itaconate; Metabolic reprogramming; Oncometabolites; Succinate; TCA cycle; Tumor immunity; α-ketoglutarate.

Fig. 1

Oncometabolite-driven reprogramming in the TCA cycle. This schematic shows how mutations in TCA cycle enzymes lead to the buildup of oncometabolites that rewire tumor metabolism. Mutant IDH converts α-ketoglutarate (α-KG) into 2-hydroxyglutarate (2-HG), while loss of SDH or FH causes succinate and fumarate accumulation. Separately, immune cells and tumor cells produce itaconate from cis-aconitate by ACOD. These oncometabolites drive cancer progression by altering metabolism, gene regulation, and immune responses

Fig. 2

Oncometabolite-driven epigenetic and metabolic dysregulation in cancer. Oncometabolites Such as 2-HG, succinate, and fumarate, which accumulate due to mutations in IDH1/2, SDH, or FH, disrupt multiple cellular pathways. These metabolites competitively inhibit α-ketoglutarate–dependent dioxygenases (α-KGDDs), including TET DNA demethylases, histone demethylases, and the RNA demethylase FTO. This leads to widespread DNA and histone hypermethylation and increased m⁶A RNA methylation, altering gene expression and blocking cell differentiation. They also induce pseudohypoxia by inhibiting prolyl hydroxylases, stabilizing HIF-1α, and activating angiogenesis and glycolysis genes (e.g., VEGF, GLUT1). Redox balance is disrupted through multiple mechanisms: succinate enhances ROS via reverse electron transport; D-2-HG depletes NADPH and glutamate, impairing glutathione synthesis; and fumarate modifies GSH via Succination, forming 2-succinyl-cysteine (2SC). Tumor cells rewire their metabolism, shifting toward fatty acid β-oxidation and glutaminolysis to compensate for impaired TCA cycle activity and reduced aspartate synthesis. Mutant IDH1 tumors rely on pyruvate carboxylase and show lipid depletion. Additionally, oncometabolites induce post-translational modifications, including succinylation, succination, and O-2HGylation, which alter protein function, DNA repair, and cytoskeletal regulation. Together, these effects promote tumor progression and create therapeutic vulnerabilities

Fig. 3

Immunomodulatory roles of TCA cycle oncometabolites in the tumor microenvironment. TCA-derived metabolites regulate immune cell behavior in cancer. α-KG enhances antigen presentation and CD8⁺ T cell Function through epigenetic remodeling. In contrast, 2-HG impairs T cell metabolism and activation, silences innate immune genes like cGAS in tumor and myeloid cells, and promotes M2 macrophage polarization. Succinate enhances immunosuppression by stabilizing HIF-1α, activating SUCNR1 signaling, and impairing T cell function through ROS and metabolic disruption. Fumarate succinates and inactivates TCR signaling proteins like ZAP70, contributing to T cell dysfunction. Itaconate, produced by myeloid cells, has dual roles: it can dampen inflammation and promote T cell exhaustion or, under specific conditions, activate antiviral signaling pathways. In tumor cells, imported itaconate stabilizes PD-L1 and protects against ferroptosis, promoting immune evasion. These combined effects create an immune-suppressive microenvironment that hinders anti-tumor immunity