Glioblastoma and resistance to radiotherapy: role of cancer stem cells subpopulations, hypoxia and therapeutic strategies.

Glioblastoma is the most aggressive primary brain tumor in adults, characterized by rapid progression, resistance to therapy, and inevitable recurrence. Despite standard treatment-surgical resection, X-ray radiotherapy, and temozolomide chemotherapy-prognosis remains poor. Growing evidence indicates that glioma stem cells (GSCs) and hypoxia drive this resistance and recurrence. This review examines distinct GSC subtypes: mesenchymal GSCs, the most aggressive and invasive; proneural GSCs, which are more radiosensitive but highly proliferative and contribute to recurrence; and slow-cycling GSCs, which, though less well understood, are of growing interest due to their activation and deactivation during radiotherapy or through as-yet-unknown mechanisms. Hypoxia, a hallmark of the glioblastoma microenvironment, maintains these stem cells in a dedifferentiated state. As a key regulator, hypoxia orchestrates radioresistance mechanisms and promotes stem-like cell persistence through processes such as epithelial-mesenchymal transition-like (EMT-like), proneural-mesenchymal transition (PMT), or the reprogramming of differentiated cancer cells into GSCs. The review concludes by highlighting therapeutic strategies under development to overcome radioresistance, including targeting GSCs, hypoxia, or employing alternative irradiation modalities beyond X-ray radiotherapy.