Nucleic acid therapeutics for reinvigorating p53 function in glioblastoma: concepts, limitations and recent advances

IDH-wildtype, high-grade glioma with predominantly astrocytic differentiation and classified as glioblastoma in the current WHO classification of central nervous system tumors is among the most common and aggressive primary malignant brain tumors. Glioblastoma remains largely refractory to current therapies, leading to early recurrence and poor prognosis. In nearly all glioblastomas, the p53 tumor-suppressor pathway is functionally inactivated, either through TP53 mutations or through deregulated signaling pathways that promote p53 degradation. This review provides a comprehensive and up-to-date overview of gene therapy strategies designed to restore p53 function or exploit p53 loss-of-function in glioblastoma. In particular, it critically discusses the biological barriers and technical limitations of viral and non-viral nucleic acid delivery systems that have contributed to inadequate clinical outcomes, while also highlighting recent advances with potential to reinvigorate p53 function in glioblastoma.