MGMT promoter methylation in glioblastoma: Molecular mechanisms, tumor microenvironment interactions, and therapeutic implications.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is associated with poor prognosis despite advances in combination therapy. Among the molecular biomarkers guiding therapeutic decision-making, O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation has emerged as clinically robust predictors of treatment response and patient survival. MGMT encodes a DNA repair enzyme that removes cytotoxic O⁶-alkylguanine lesions generated by alkylating agents such as temozolomide (TMZ). Epigenetic silencing of MGMT through promoter CpG islands methylation decreases DNA repair capacity and enhances tumor sensitivity to TMZ therapy. This narrative review summarizes current advances in the molecular mechanisms, tumor microenvironment (TME) interactions, and therapeutic applications of MGMT promoter methylation in GBM. Particular emphasis is placed on the epigenetic regulation of MGMT, including the roles of DNA methyltransferases, histone modifications, chromatin remodeling, and non-coding RNAs in controlling gene expression. The dynamic and heterogeneous nature of MGMT methylation and its association with key molecular alterations, including isocitrate dehydrogenase (IDH) mutations and the glioma CpG islands methylator phenotype, are also discussed. Accumulating evidence indicates that MGMT methylation reshapes the immune and metabolic landscape of the GBM microenvironment through effects on immune cell infiltration, macrophage polarization, cytokine signaling, and hypoxia-driven epigenetic remodeling. Emerging studies further highlight its central role in coordinating epigenetic, immune, and metabolic pathways associated with therapeutic resistance in GBM. Building on these mechanistic insights, this review discusses emerging strategies to overcome MGMT-mediated resistance, including next-generation alkylating agents, epigenetic modulators, combination immunotherapies, and radiogenomic approaches for precision medicine. Understanding MGMT methylation biology may improve patient stratification and support precision-based therapeutic interventions in GBM.