The immune awakening: Transformative strategies against brain tumors

Glioblastoma multiforme remains the primary brain tumor with the highest mortality rate, which is highly resistant to aggressive conventional therapies, owing to its capacity to evade the central nervous system's distinctive immunological barriers. Several mechanisms confer this tumor resistance, such as down-regulation of MHC molecules, secretion of immunosuppressive cytokines, metabolic reprogramming, recruitment of Tregs and myeloid-derived suppressor cells, and heterogeneity reinforced by the blood-tumor barrier and hypoxia. The purpose of this review is to examine the changing field of neuroimmunology, emphasizing the interactions between the immune system and the central nervous system (CNS), immunological resistance mechanisms in GBM, and new developments in immunotherapeutic approaches. A comprehensive literature search was conducted from inception till May 2025 on PubMed, Google Scholar, Cochrane and Clinicaltrials.gov to find relevant studies. The recent findings show that CNS is a highly regulated environment with controlled populations of resident and infiltrating immune cells. GBM exploits these immune barriers through various mechanisms, ultimately creating an immunosuppressive tumor microenvironment. Cancer vaccines, immune checkpoint inhibitors, adoptive cell therapies, and oncolytic viruses, show promise but face challenges like limited BBB penetration, immune suppression, and tumor heterogeneity. The role of the gut microbiome and combinatorial strategies are increasingly recognized as vital in overcoming immunotherapy resistance. Nevertheless, continued research is essential to better understand and thereby overcome resistance and improve clinical outcomes in GBM patients.