p53 Pathway-Targeted Therapeutic Strategies in Glioblastoma: A CNS-Specific Framework Integrating Therapeutic Resistance, Molecular Stratification, CNS Pharmacology, and Clinical Translation.

Glioblastoma (GBM) remains one of the most difficult therapeutic problems in adult neuro-oncology. Its resistance to treatment reflects not only malignant cellular biology but also central nervous system-specific constraints, including blood-brain barrier and blood-tumor barrier heterogeneity, diffuse infiltrative growth, uncertain target-site exposure, treatment-induced evolution, and the need to preserve neurological function. The tumor suppressor p53, encoded by TP53, is highly relevant to glioblastoma because it regulates cell-cycle arrest, DNA repair, apoptosis, senescence, genomic stability, and cellular responses to radiotherapy and temozolomide. However, p53 pathway-targeted therapy in glioblastoma cannot be translated by simply extrapolating from extracranial solid tumors. This narrative review develops a CNS-specific translational framework for p53 pathway-targeted therapy in GBM. The framework integrates molecular dependency, unbound brain exposure and intratumoral distribution, pharmacodynamic confirmation, molecular stratification, and neuro-oncology-specific clinical endpoints. We discuss how distinct p53 pathway states, including TP53 mutation, MDM2/MDM4-mediated suppression, and downstream apoptotic competence, influence therapeutic vulnerability and biomarker-guided clinical development. Among current strategies, MDM2-axis inhibition in TP53-wild-type glioblastoma appears to be one of the most mechanistically tractable approaches, with emerging GBM-specific translational evidence, although clinical efficacy remains to be established. Other mutant p53-directed, network-based, gene-, immune-, and combination strategies remain less mature and require stronger glioblastoma-specific evidence. Future progress will depend on aligning target biology with CNS drug delivery, tissue pharmacokinetics/pharmacodynamics, biomarker-enriched trial design, and clinically meaningful neurological outcomes.