Isocitrate dehydrogenase (IDH)-mutant low-grade gliomas are slow-growing brain tumors that frequently progress to aggressive high-grade gliomas that have dismal outcomes. In a recent study, Wu and colleagues provide critical insights into the mechanisms underlying malignant progression by analyzing single-cell gene expression and chromatin accessibility across different tumor grades. Their findings support a two-phase model: In early stages, tumors are primarily driven by oligodendrocyte precursor-like cells and epigenetic alterations that silence tumor suppressors like CDKN2A and activate oncogenes such as PDGFRA. As the disease advances, the tumors become sustained by more proliferative neural precursor-like cells, in which genetic alterations, including PDGFRA, MYCN, and CDK4 amplifications and CDKN2A/B deletion, drive tumor progression. The study further highlights a dynamic regulation of IFN signaling during progression. In low-grade IDH-mutant gliomas, IFN responses are suppressed through epigenetic hypermethylation, which can be reversed with DNA methyltransferase 1 inhibitors or IDH inhibitors, leading to reactivation of the IFN pathway. In contrast, higher grade gliomas evade IFN signaling through genetic deletions of IFN genes. These findings emphasize a broader epigenetic-to-genetic shift in oncogenic regulation that drives glioma progression, provide a valuable framework for understanding the transition from indolent tumors to lethal malignancies, and have implications for therapy and clinical management.