DNMTi in Overcoming Immunosuppression in Glioblastoma: Mechanisms and Therapeutic Potential

Glioblastoma (GBM) is the most aggressive primary malignancy of the central nervous system, characterized by poor prognosis and limited therapeutic options. Epigenetic dysregulation, particularly aberrant DNA methylation, plays a pivotal role in glioblastoma pathogenesis by modulating tumor suppressor genes and oncogenes. The corresponding epigenetic writers and erasers, DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, maintain methylation homeostasis, and alterations in their activity can cause abnormal gene expression that drive glioblastoma progression. DNMT1 preserves methylation patterns during DNA replication, whereas DNMT3A and DNMT3B establish de novo methylation. The glioma CpG island methylator phenotype (G-CIMP), an epigenetic subtype of glioblastoma, is frequently associated with mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), which impair TET-mediated demethylation and result in widespread hypermethylation. Moreover, altered methylation contributes to drug resistance, exemplified by temozolomide (TMZ) resistance mediated through SNHG12 hypomethylation. Currently, two DNMT inhibitors, 5-azacytidine and decitabine, are FDA-approved for certain cancers, while several novel agents, including zebularine, hydralazine and MA17, are under investigation. Although these emerging drugs show promise, their clinical utility remains limited by issues of stability, cytotoxicity and therapy resistance. Understanding the interplay between DNA methylation, tumor progression, and therapy resistance is important to develop new precision medicine strategies in glioblastoma.