Alterations in 3D Chromatin Spatial Organisation in Tumourigenesis and Therapy Resistance of Glioblastoma: The Recent Advances in Understanding Molecular Mechanisms, Clinical Implications, and Therapeutic Perspectives

Glioblastoma (GBM) remains one of the most aggressive and lethal forms of brain cancer, characterised by profound genetic, epigenetic, and phenotypic heterogeneity. Recent advancements in high-resolution genome mapping have unveiled the critical role of three-dimensional (3D) chromatin architecture—encompassing chromatin loops, topologically associating domains, and enhancer–promoter interactions—in driving GBM tumourigenesis and therapy resistance. This review summarises recent insights into the mechanistic contribution of 3D genome reorganisation in sustaining oncogenic transcriptional programs, promoting intratumoural heterogeneity, and facilitating adaptive resistance. We integrate molecular discoveries with clinical and therapeutic perspectives, emphasising the potential of epigenetic drugs to target disease-associated chromatin structures. Finally, we highlight unresolved questions and future directions in leveraging chromatin conformation data for precision oncology in GBM.