The Gut–Brain–Immune Axis in Glioma: Emerging Mechanisms and Therapeutic Opportunities

Gliomas, particularly glioblastomas, represent some of the most treatment-resistant cancers due to their profoundly immunosuppressive tumor microenvironment (TME) and the restrictive nature of the blood–brain barrier. While recent advances in immunotherapy have transformed the treatment landscape for peripheral tumors, success in gliomas remains limited. Emerging evidence suggests that the gut microbiota—through the gut-brain-immune axis—may play a significant role in shaping systemic and central immune responses. Gut-derived microbial metabolites, immune cell modulation, and neuro-immune signaling pathways have been shown to influence microglial activation, T cell infiltration, and even response to immune checkpoint inhibitors (ICIs) such as PD-1 and emerging targets like TIM-3, LAG-3, and TIGIT. Furthermore, the efficacy and persistence of CAR-T and CAR-NK therapies may also be impacted by microbial composition, offering a novel avenue for therapeutic optimization. This review explores the biological underpinnings of the gut-brain-immune axis in glioma, summarizes key preclinical and clinical findings, and highlights the potential of gut microbiota modulation—via probiotics, engineered microbes, or fecal microbiota transplantation (FMT)—as an adjunct to immunotherapy. We also discuss technical and translational challenges, including interindividual variability and mechanistic uncertainty. Understanding the dynamic crosstalk between the gut and the glioma immune microenvironment may unlock new therapeutic strategies and improve outcomes in this highly lethal disease.