Mapping epigenetic alterations across brain tumor hallmarks

Central nervous system tumors represent a heterogeneous group of diseases, mainly localized in the brain. Among them, malignant brain tumors represent some of the most aggressive cancers. In adults, only approximately 30% of patients diagnosed with glioblastoma survive beyond two years. Similarly, several pediatric-predominant brain tumors, including medulloblastoma, diffuse intrinsic pontine glioma, and ependymoma, remain among the deadliest solid tumors in children. Therefore, a deeper understanding of brain tumor biology is imperative for the development of more effective therapeutic strategies. Dysregulated epigenetic control has emerged as a critical driver of brain tumor initiation and progression, influencing malignant phenotypes across multiple stages of the disease. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, regulate gene expression programs that contribute to all hallmarks of cancer by modulating the activity of tumor suppressor genes and oncogenes. Given the central role of epigenetics in brain tumorigenesis and the potentially reversible nature of these alterations, epigenetic mechanisms represent particularly attractive therapeutic targets. Although several epigenetic drugs have shown promising results in preclinical and clinical studies, their clinical application remains constrained by a limited knowledge of the brain tumor epigenome and by challenges related to tumor location and drug delivery. In this review, we summarize key epigenetically regulated genes and dysregulated microRNAs across major brain tumor types and link these alterations to specific cancer hallmarks. We further highlight representative examples of epigenetic therapies whose effects converge on hallmark-associated oncogenic processes.