Contemporary Advances and Challenges in the Treatment of Glioblastoma (GBM) : The role of Immunotherapy and Small-Molecule Inhibitors as potential therapeutic strategies

Glioblastoma Multiforme (GBM) is the most common malignant primary tumor of the Central NervousSystem, accounting for the majority of tissue brain tumors and CNS neoplasms. GBM has an incidencerate of 3.2 per 100,000 people in the United States, with an abysmal survival rate of 15 months withtreatment and under three months for untreated patients. GBM remains incurable, with nodisease-modifying treatment available. As a grade IV astrocytoma, GBM is highly aggressive,characterized by rapid proliferation, high metabolic demands, substantial angiogenesis, and diffuseinfiltration of healthy parenchyma. The GBM genome is highly heterogeneous, with unpredictableamplification patterns, dysregulation, and mutational activation of RTK genes, tumor suppressor genes,and growth factor signalings. GBM's indistinct tumor margins, its highly adaptive interaction with thebrain microenvironment, and the existence of the BBB/BBTumor barrier further limit effective anti-GBMtherapeutic strategies. Hence, anti-GBM drug discoveries and molecular techniques that aim forpatient-specific treatment stratification are of profound clinical and therapeutic significance. The current paper aims to outline the fundamental pathophysiology, tumorigenicity, and immunosuppressive mechanism of GBMs, review current treatment options for GBMs, and examine the contemporary challenges and advances in anti-GBM drug discovery and delivery. Lastly, the paper aims to shed light on the emergence of Small-Molecule Inhibitors, Immune checkpoint Inhibitors, and vaccination therapy as potentially efficacious therapeutic strategies for treating GBM.