Integrating Molecular Pathology, Tumor Microenvironment, and Novel Therapies to Overcome Resistance in Glioblastoma

Glioblastoma multiforme (GBM) represents the most aggressive primary brain tumor in adults, characterized by significant heterogeneity, rapid progression, and resistance to existing therapies. Conventional therapies provide minimal survival advantages due to recurrence influenced by glioma stem-like cells (GSCs), adaptive signaling pathways, and a highly immunosuppressive tumor microenvironment (TME). Further, molecular profiling has revealed significant alterations, including EGFR amplification, IDH mutations, MGMT promoter methylation, and TERT promoter changes; however, challenges persist in the integration of genomic, epigenetic, metabolic, and transcriptomic data for the development of effective therapies. Thus, this review examines the limitations by integrating recent developments in molecular classification, dysregulated signaling pathways, metabolic reprogramming, and non-coding RNA-mediated regulation in GBM. Additionally, the manuscript emphasizes novel therapeutic strategies, such as nanomedicine, oncolytic virotherapy, immunotherapy, tumor-treating fields, and phytochemical-based interventions, as well as the increasing significance of artificial intelligence and machine learning in diagnosis and personalized treatment. Lastly, this review integrates mechanistic and translational insights to establish a framework addressing blood–brain barrier limitations, therapeutic resistance, and immune evasion, thereby facilitating the advancement of precision medicine approaches for enhanced GBM outcomes.