Niche-specific epigenetic interventions in the spatially heterogeneous glioblastoma microenvironmental landscape: strategies for radiotherapy enhancement

Glioblastoma (GBM) remains incurable, largely due to inherent radiotherapy resistance driven by synergistic crosstalk between spatial heterogeneity and epigenetic dysregulation. Distinct tumor microenvironments-hypoxic cores, invasive edges, and perivascular regions-harbor glioblastoma-initiating cells (GICs) with unique epigenetic traits that promote radiation evasion: hypoxic cores activate the HIF-SIRT axis to maintain quiescence; invasive edges employ EZH2-mediated H3K27me3 to drive proneural-mesenchymal transition (PMT); and perivascular niches utilize HDAC-DNA repair and BRD4-super-enhancer mechanisms to sustain stemness. Concurrent epigenetic alterations-such as MGMT promoter methylation, aberrant histone modifications, and chromatin remodeling-further enhance adaptive plasticity. This review synthesizes recent preclinical and clinical evidence (2019-2024) to delineate how spatial and epigenetic mechanisms form a "resistance loop" that subverts radiotherapy. We argue that effective radiosensitization requires niche-specific strategies: HDAC inhibitors in hypoxic regions to impair DNA repair, EZH2 inhibitors at invasive margins to suppress PMT, and BET inhibitors in perivascular zones to target stemness programs. We propose a "spatial-epigenetic precision pipeline" involving: (1) mapping niche-specific epigenetic signatures <i>via</i> spatial multi-omics; (2) developing ligand-functionalized nanocarriers for targeted delivery; and (3) designing adaptive combinatory regimens (epigenetic agents with radiotherapy and immunotherapy) based on dynamic response monitoring. This framework aims to disrupt spatial-epigenetic crosstalk, potentially transforming GBM into a chronically manageable disease.