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Glioblastoma (GB) remains a formidable challenge in oncology, with current treatment approaches providing only marginal improvements in patient outcomes. Despite significant advances in understanding its molecular and genetic characteristics, median survival for untreated patients remains distressingly low, emphasizing the urgent need for novel therapeutic strategies. This review comprehensively examines the standard first-line treatments for GB, including surgery, concomitant radio-chemotherapy, and maintenance chemotherapy, while highlighting the limitations of these approaches. Consequently, we explore emerging novel therapeutic modalities such as Oncolytic Viral Therapy with genetically modified oncolytic viruses that enhance the capabilities of antigen-presenting cells. These cells migrate to lymph nodes to recruit cytotoxic CD8+ T lymphocytes, directing them to the site of infection where they eradicate cells that promote tumour growth. Aptamer-based therapies, such as GMT-3, AS1411, GS24, GMT8, and Gint4.T, which exhibit specificity for their biological targets and can act as drug transporters by facilitating receptor-mediated transcytosis within the endothelial cells of the blood-brain barrier, thus improving drug delivery. Tumour-treating fields (TTFields) that have shown increased overall survival rates in patients. Personalized genomic medicine, driven by biomarkers, which provokes immune responses tailored to the tumour’s specific antigens, thereby customizing patient-specific treatments to improve effectiveness. By synthesizing current evidence and recent breakthroughs, we underscore the potential use of advancing novel therapies to address the unmet clinical needs of GB patients and ultimately enhance their overall survival and quality of life.
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