The TET Protein Family in Gliomas: Epigenetic Regulation, Molecular Pathogenesis, and Therapeutic Opportunities

Epigenetic dysregulation is a defining feature of glioma pathogenesis, with aberrant DNA methylation contributing to tumor initiation, cellular plasticity, progression, and therapeutic resistance. The ten-eleven translocation (TET) family of dioxygenases (TET1, TET2, and TET3) catalyzes the 5-methylcytosine (5mC) oxidation to 5-hydroxymethylcytosine (5hmC) and subsequent intermediates, inducingactive DNA demethylation and regulating organization of chromatin and gene expression. In gliomas, particularly those harboring isocitrate dehydrogenase (IDH) mutations, accumulation of the 2-hydroxyglutarate oncometabolite suppresses TET activity, leading to widespread epigenetic remodeling, the glioma CpG island methylator phenotype and impaired cellular differentiation. Emerging evidence demonstrates that individual TET isoforms exert distinct and context-dependent biological functions. Although TET1, TET2, and TET3 have been involved in the regulation of glioma biology, their effects may vary depending on the cellular and molecular context, with individual isoforms exhibiting distinct and, in some cases, opposing effects on glioma behavior. This review summarizes current knowledge regarding the molecular mechanisms governing TET dysregulation in gliomas, including their interactions with metabolic alterations, chromatin remodeling, the tumor microenvironment, and immune evasion. Recent advances in methodologies for assessing TET activity and 5hmC levels are also discussed along with the possible integration of TET-associated biomarkers into molecular glioma classification, and emerging therapeutic strategies to restore or selectively modulate TET function.