Next-generation therapeutics for glioblastoma: Challenges and future directions.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Although recent World Health Organization classifications integrating molecular features have improved diagnostic precision, therapeutic outcomes for IDH-wild-type glioblastoma remain dismal. Standard treatment with radiotherapy and temozolomide has changed little over the past two decades, and most investigational therapies have failed to produce durable clinical benefit. Tumor heterogeneity, adaptive resistance mechanisms, a profoundly immunosuppressive tumor microenvironment, and limited drug delivery across the blood-brain barrier have collectively contributed to these failures. This review summarizes the evolving molecular landscape of glioblastoma and examines emerging therapeutic approaches designed to overcome these barriers. We discuss advances in molecularly targeted therapies, including strategies directed at BRAF and FGFR alterations, as well as continued efforts to address EGFR-driven disease. We also review immunotherapeutic approaches such as immune checkpoint inhibition, chimeric antigen receptor T-cell therapies, and oncolytic viruses, highlighting key clinical trial results and biological challenges. In parallel, we explore metabolic targeting strategies and novel technologies aimed at improving central nervous system drug delivery, including focused ultrasound and convection-enhanced delivery. Collectively, current evidence indicates that meaningful progress in glioblastoma will require biomarker-driven patient selection, rational combination strategies, and improved methods for intracranial drug delivery. While substantial challenges remain, ongoing translational and clinical efforts provide a framework for the development of more effective and personalized therapeutic strategies.