Innovative radiotherapies for the treatment of glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid progression, extensive inter- and intra-tumoral heterogeneity, and resistance to standard-of-care, including radiotherapy. Radiotherapy remains a cornerstone of GBM management, but its efficacy is limited by complex tumor biology and mechanisms of radioresistance. This review explores the advances in radiotherapy for GBM, focusing on the interplay between tumor biology and emerging treatment strategies. Hallmarks of GBM biology, including hypoxia, the robust DNA repair mechanisms, the immunosuppressive tumor microenvironment (TME), and the extensive plasticity contribute to therapeutic resistance. Innovative approaches in radiotherapy may allow to address these challenges. Charged particle therapies (CPTs), including proton and carbon ion therapy, offer superior precision and enhanced biological effectiveness by delivering lethal doses to tumor cells while sparing surrounding healthy tissue. FLASH therapy, using ultra-high dose rates, could reduce normal tissue toxicity without compromising tumor control. Furthermore, targeted radionuclide therapy harnesses tumor-specific targets to systemically deliver radiopharmaceuticals carrying therapeutic radionuclides directly to cancer cells, improving specificity and reducing off-target effects. This review highlights the promise of these novel radiotherapy modalities to address GBM's inherent heterogeneity and treatment resistance. By integrating advancements in technology with novel insights into GBM biology, these approaches may significantly improve patient outcomes.