Unlocking glioblastoma: breakthroughs in molecular mechanisms and next-generation therapies

Abstract

Glioblastoma (GB) remains the most aggressive primary brain tumor in adults, characterized by rapid progression, recurrence, and resistance to conventional therapies. Despite advancements in surgical resection, radiation, and chemotherapy, long-term survival rates remain low. This review comprehensively explores GB's molecular classification, pathological mechanisms, epidemiology, and emerging therapeutic strategies. Key genetic mutations in TP53, MAPK/ERK, PI3K/AKT/mTOR, and many more signaling pathways, such as Notch, Wnt, Hedgehog, TGF-β, and NF-κB drive tumor progression, therapy resistance, and immune evasion. Diagnostic advances, including multi-modal imaging and molecular profiling, have improved early detection and precision therapy selection. Conventional treatments such as temozolomide and radiation therapy provide modest benefits, but novel approaches offer promising alternatives. Immunotherapy, targeting checkpoint inhibitors and tumor vaccines, has emerged as a potential avenue for enhancing tumor control. Nanotechnology-based drug delivery, particularly liposomal formulations and CRISPR-Cas9 gene editing improves blood-brain barrier penetration and reduces systemic toxicity. Targeted inhibitor-based therapies, including angiogenesis inhibitors, help limit tumor vascularization. Furthermore, a systematic review of 16 clinical trials highlights the emerging trends in combinatorial strategies, their adverse events, and outcomes, which remain pivotal for optimizing GB management. This review synthesizes current research while emphasizing future directions that could revolutionize GB therapeutic approaches and improve patient survival.

Keywords: Glioblastoma; Immunotherapy; Systematic review; Targeted therapy; Therapeutic resistance; Tumor microenvironment.

Fig. 1

Flow Diagram for Study Selection The flow diagram represents the systematic review of studies, detailing the number of records identified, screened, excluded, and included in the final analysis

Fig. 2

Classification of the glioma within each tumor type, based on molecular and genetic characteristics It categorizes gliomas into three primary groups: adult-type diffuse gliomas, pediatric-type diffuse gliomas, and circumscribed gliomas. GB falls under Grade IV adult-type diffuse gliomas, demonstrating high aggressiveness and recurrence rates [18]

Fig. 3

Schematic representation of dysregulation of key signaling pathways in GB This diagram illustrates the disruption of the T cell receptor, receptor tyrosine kinase (RTK)/MAPK/ERK, and P13K/Akt/mTOR signaling cascades in GB. The unusual activation of these pathways distorts cellular processes and impairs axonal transport, gene transcription, cell proliferation, mitochondrial function, and apoptosis of cells. The cumulative effect of these molecular alterations leads to tumorigenesis in GB [73, 74]