The Role of Gut Microbiome on Glioblastoma Oncogenesis and Malignant Evolution

Abstract

Glioblastoma (GBM) remains the most aggressive primary brain tumor, with poor survival outcomes and treatment limited to maximal safe surgical resection, chemotherapy with temozolomide, and radiotherapy. While immunotherapy and targeted treatments show promise, therapeutic resistance and disease progression remain major challenges. This is partly due to GBM's classification as a "cold tumor" with low mutational burden and a lack of distinct molecular targets for drug delivery that selectively spare healthy tissue. Emerging evidence highlights the gut microbiota as a key player in cancer biology, influencing both glioma development and treatment response. This review explores the intersectionality between the gut microbiome and GBM, beginning with an overview of microbiota composition and its broader implications in cancer pathophysiology. We then examine how specific microbial populations contribute to glioma oncogenesis, modulating immune responses, inflammation, and metabolic pathways that drive tumor initiation and progression. Additionally, we discuss the gut microbiome's role in glioma therapeutic resistance, including its impact on chemotherapy, radiotherapy, and immunotherapy efficacy. Given its influence on treatment outcomes, we evaluate emerging strategies to modulate gut flora, such as probiotics, dietary interventions, and microbiota-based therapeutics, to enhance therapy response in GBM patients. Finally, we address key challenges and future directions, emphasizing the need for standardized methodologies, mechanistic studies, and clinical trials to validate microbiota-targeted interventions in neuro-oncology. By integrating gut microbiome research into GBM treatment paradigms, we may unlock novel therapeutic avenues to improve patient survival and outcomes.

Keywords: glioblastoma; gut microbiome; gut–brain axis; therapeutic resistance.

Figure 1

Schematic representation of immune dysfunction in GBM. This figure illustrates how GBM suppresses the immune system by impairing T cell function, NK cell function, and inducing macrophage polarization. The arrows depict the interdependence between immunosuppressive pathways, particularly the feedback loop between Tregs and M2 macrophages, emphasizing how GBM reprograms the immune microenvironment to evade anti-tumor immunity.

Figure 2

Schematic representation of gut microbiota, metabolites, and immune modulators in glioblastoma progression, illustrating the role of different bacterial groups, metabolites, and immune modulators in promoting glioblastoma (GBM) progression. The interconnected gears symbolize the dynamic and complex interplay between these factors, even though direct evidence for their interactions remains to be proven. Blue gear (gut bacterial components): highlights bacterial groups such as Rikenellaceae, Victivallaceae, Ruminococcaceae, and Lactococcus, which influence immune responses and tumor progression through their interactions with the immune system and metabolites. Red gear (metabolites): showcases key metabolites, including butyrate, arginine, glutamate, serotonin, and dopamine. These metabolites are critical for immune regulation, tumor metabolism, and modulation of the tumor microenvironment. Orange gear (immune modulators): highlights immunosuppressive factors such as IDO, CCL2, TIM4, STAT3, TGF-β, AhR, CTLA-4, and PD-L1, which enable glioblastoma cells to evade immune detection and foster an immunosuppressive environment.