Gut microbiome-mediated modulation of the glioblastoma tumor microenvironment for enhanced immunotherapy response: Mechanistic insights and future perspectives.

Glioblastoma (GBM) is known to be one of the most aggressive and deadly brain tumors in adults, with a very poor prognosis. An immunosuppressive tumor microenvironment, the blood-brain barrier's (BBB's) protective nature, and genetic heterogeneity mediate resistance to conventional treatments, such as immune checkpoint inhibitors. Recent studies have shed light on the important role of the gut-brain axis in regulating GBM pathogenesis. Studies have demonstrated that patients with GBM frequently exhibit gut dysbiosis, with limited beneficial microbial populations, thereby enhancing immunosuppression and reducing the effectiveness of immune checkpoint inhibitors. This is mediated by SCFAs derived from the gut microbiota, such as acetate, propionate, and butyrate, which influence CNS immunity through direct effects on immune cells and processes, including HDAC inhibition. SCFAs can enhance the proliferation of anti-inflammatory T regulatory cells, promote pro-inflammatory responses from microglia and tumor-associated macrophages, and fortify the integrity of the BBB. Also, certain bacteria belonging to the genera Blautia and Bifidobacterium have been found to enhance the recruitment of anti-tumor CD8+ cytotoxic T lymphocytes. Thus, FMT, probiotics, prebiotics, and high-fiber diets are very promising adjuvant strategies to overcome GBM resistance by therapeutically enhancing the gut microbiome. This will aid in restoring microbial resilience, optimizing SCFA production, and potentiating anti-tumor immune responses. To validate microbial biomarkers and causative pathways, future advances in this field will integrate multi-omics data with robust clinical trials. Moreover, to examine how the gut microbiome influences the glioblastoma tumor microenvironment and the response to immunotherapy, this narrative review synthesizes existing data from studies of GBM patients, experimental models, and neuroimmunology research.