Central nervous system (CNS) tumors consist of a diverse set of malignancies that remain clinically challenging due to their biological complexity, high morbidity, and limited responsiveness to current therapies. A growing body of genomic evidence has revealed that dysregulation of the mitogen-activated protein kinase (MAPK) signaling pathway is a recurrent and unifying characteristic across many pediatric and adult CNS tumor entities. Alterations affecting upstream receptor tyrosine kinases (RTKs), RAS GTPases, RAF kinases, and other associated regulators contribute to MAPK signaling pathway hyperactivation, shaping tumor behavior, therapy response and resistance. These aberrations ranging from hotspot mutations such as BRAF V600E and oncogenic fusions like BRAF–KIAA1549 are particularly enriched in gliomas and glioneuronal tumors, highlighting MAPK signaling as a key oncogenic driver. The expanding availability of molecularly targeted compounds, including selective inhibitors of RAF, MEK and ERK, has begun to transform treatment approaches for specific molecular subtypes. However, the clinical benefit of MAPK-directed therapies is frequently limited by restricted blood–brain barrier (BBB) penetration, intratumoral heterogeneity, parallel pathway reactivation, and an immunosuppressive tumor microenvironment (TME). In this review, we synthesize current knowledge on MAPK pathway alterations in CNS tumors and evaluate the therapeutic landscape of MAPK inhibition, with emphasis on approved agents, emerging compounds, combination strategies, and novel drug-delivery technologies. We also discuss mechanisms that undermine treatment efficacy and highlight future directions aimed at integrating MAPK-targeted therapy into precision-based management of brain tumors.

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.