Epigenetic deregulation in adult gliomas: A key driver of molecular heterogeneity and precision oncology.

Gliomas, particularly glioblastoma, are characterized by profound molecular and cellular heterogeneity that drives tumor progression, therapeutic resistance, and poor clinical outcomes. Increasing evidence indicates that epigenetic deregulation, extending beyond genetic alterations, plays a central role in glioma initiation, evolution, and treatment response. This review summarizes current advances in the epigenetic landscape of adult gliomas with particular emphasis on the interplay between DNA methylation, histone modifications, chromatin remodeling and their contributions to molecular heterogeneity and precision neuro-oncology. We discuss key epigenetic mechanisms, including global DNA hypomethylation, promoter CpG island hypermethylation, histone acetylation and methylation and their effects on genome stability, transcriptional regulation, stemness, immune modulation, metabolic reprogramming, and therapeutic resistance. Clinically relevant biomarkers, including O6-methylguanine-DNA methyltransferase promoter methylation and the glioma CpG island methylator phenotype, are highlighted alongside emerging therapeutic targets such as histone deacetylases, Enhancer of Zeste Homologue 2, G9a, and protein arginine methyltransferase 5. We further examine the impact of spatial and temporal epigenetic heterogeneity on biomarker interpretation and treatment selection, as well as recent advances in methylation-based tumor classification. Collectively, this review highlights epigenetic deregulation as both a fundamental driver of adult glioma biology and a promising foundation for precision oncology.