Targeting glioblastoma epigenetics: mechanisms, microenvironmental interplay, and therapeutic potential

Glioblastoma (GBM) is an intricate intracranial tumor that has cataclysmic outlook. It originates from glial cells having an average life expectancy of one and a half years. Despite intensive multimodal therapy, the tumor's innate invasiveness and cellular heterogeneity lead to nearly inevitable recurrence. Recent advancements have shifted the focus toward the interplay between genetic drivers and the dynamic epigenetic landscape. WHO classification defined GBM as an IDH-wildtype tumor, distinguishing it from IDH-mutant. Present review explores the complex epigenetic mechanisms such as DNA methylation, histone modification and RNA editing that drive GBM progression, shape the tumor microenvironment and facilitate immune evasion. The review further discusses severe translational barriers, including blood brain barrier penetrance, tumor heterogeneity, and the immunosuppressive effects of steroids. Finally, we highlight the therapeutic potential of targeting these epigenetic vulnerabilities through inhibitors of histone deacetylase and DNA methyltransferase, either alone or combined with modern immunotherapies to overcome treatment resistance and improve patient outcomes.