Abstract Glioblastoma is a highly aggressive primary brain tumour marked by extensive genomic and epigenomic alterations, cellular heterogeneity, and therapeutic resistance. Despite maximal surgical resection followed by chemoradiotherapy, median survival remains approximately 15 months, reflecting the tumour’s invasive behaviour and adaptability. Advances in molecular oncology have revealed two promising therapeutic directions: epigenetic reprogramming and neurogenetic modulation. Glioblastoma exhibits widespread epigenetic dysregulation that disrupts transcriptional control, enhances cellular plasticity, and drives tumour progression. Concurrently, glioma cells aberrantly reactivate developmental programmes, acquiring neural stem cell-like states governed by transcription factors and signalling networks such as SOX2, OLIG2, Notch, and Wnt. These pathways collectively sustain stemness, lineage mimicry, and therapy resistance. This review proposes a focused conceptual framework centred on epigenetic and neurogenetic modulation as two core regulatory layers shaping glioblastoma plasticity and adaptive resistance. We highlight how DNA methylation, histone modifications, and chromatin remodelling contribute to transcriptional dysregulation, and how neurodevelopmental signalling reinforces malignant plasticity. Emerging preclinical and clinical studies combining epigenetic inhibitors with differentiation- or reprogramming-based therapies are discussed. By uniting mechanistic insights from chromatin biology, neurodevelopment, and cancer therapeutics, this integrative conceptual framework offers a structured lens for targeting key vulnerabilities underlying glioblastoma plasticity. The integration of these complementary strategies offers potential to enhance therapeutic responsiveness and improve disease management in this devastating malignancy.
Yüncü et al. (Tue,) studied this question.
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