The TET/5hmC mediated epigenetic landscape in glioma: From molecular mechanisms to therapeutic targeting and future perspectives

The DNA hydroxymethylation landscape is profoundly disrupted in gliomas, especially glioblastoma, marked by global loss of 5-hydroxymethylcytosine (5hmC) and impaired Ten-eleven translocation (TET) enzyme activity. This review synthesizes evidence that TET family expression and subcellular localization are systematically altered in glioma: TET1 undergoes nuclear exclusion, while TET2 and TET3 show reduced nuclear abundance, directly contributing to 5hmC depletion. The extent of 5hmC loss correlates with tumor grade yet exhibits subtype heterogeneity, including a unique "5hmC-high" glioblastoma subgroup, highlighting the importance of post-transcriptional control of TET protein levels. Upstream regulatory mechanisms involve transcription factors (e.g., SOX2-mediated repression and context-dependent STAT3 activation), non-coding RNAs (such as miR-10b), and epigenetic silencing of TET genes themselves, alongside metabolic and microenvironmental constraints (e.g., D-2-HG from IDH1/2 mutations, hypoxia) that restrict TET catalytic function. Downstream consequences include TET deficiency-driven promoter hypermethylation and MBD-mediated repression of tumor suppressor and differentiation genes, RNA hydroxymethylation-dependent regulation of mRNA stability and splicing, and chromatin reprogramming via interactions with complexes like OGT/COMPASS and PRC2. Functionally, TET inactivation promotes tumor initiation and progression, sustains glioma stem cells, enhances cellular plasticity, drives metabolic reprogramming, and facilitates immune evasion. Emerging therapeutic strategies encompass miRNA antagonists, vitamin C as a TET cofactor, DNMT and HDAC inhibitors, locus-specific epigenetic editing tools (e.g., CRISPR-dCas9 and engineered demethylases), brain-penetrant IDH inhibitors, and novel approaches such as PROTACs and TET mRNA delivery-all requiring precision application due to the context-dependent roles of TET proteins. We further identify critical research gaps, including single-cell and spatial mapping of TET/5hmC dynamics, microenvironmental regulation of TET activity, functional cooperation between TET isoforms, and the development of clinically feasible delivery systems and biomarkers. Addressing these challenges will be essential to translate TET pathway modulation into effective, individualized combination therapies for glioma patients.