Platinum-based therapeutics as emerging multi-modal radiosensitizers in glioblastoma treatment

Glioblastoma (GBM) is a highly lethal brain cancer with poor patient prognosis and limited treatment options. Standard-of-care therapy involves maximally safe surgical resection followed by radiation therapy (RT) in combination with the alkylating agent temozolomide (TMZ) to treat the residual and brain-invading components of the disease. While RT remains a central part of definitive treatment, its efficacy is limited by intrinsic and acquired radiation resistance, making long-term tumor control and survival rare. While TMZ provides modest anti-tumor benefits, tumor resistance to TMZ and lack of synergy with RT underscore the critical need to identify novel therapeutic strategies that can enhance RT efficacy. Platinum-based chemotherapeutics have emerged as promising radiosensitizers due to their ability to augment RT-induced DNA double-strand breaks, while also triggering oxidative stress, endoplasmic reticulum stress, immunogenic cell death, and apoptosis. Such multimodal mechanisms of action may propel platinum-based drugs to the forefront of GBM treatment and overcome the adaptive survival pathways that underlie radiation resistance. This is particularly the case as advances in drug delivery strategies, such as liposome- and nanocomplex-based formulations, are being developed to improve brain penetration, tumor accumulation, and reduce systemic toxicity-critical challenges that have historically limited the clinical application of platinum-based drugs in GBM. This review provides clinical relevance, mechanisms, delivery strategies, challenges, and recent advancements in the use of platinum compounds as radiosensitizers for GBM treatment, highlighting key preclinical studies, clinical observations, and future directions.