The Microbiome in Glioblastoma: Mechanisms, Tumor–Immune Interactions, and Translational Perspectives

Abstract

ABSTRACT Despite multimodal treatment, glioblastoma (GBM) remains difficult to control because of diffuse invasion, tumor heterogeneity, immune dysfunction, and frequent recurrence. Increasing attention has focused on whether intestinal microbial communities and their products can modify systemic and central nervous system processes relevant to GBM. This narrative review critically evaluates current evidence linking microbial communities, microbial metabolites, tumor‐associated microbial signals, and host immune responses with GBM biology and clinical translation. PubMed, Scopus, Web of Science, and Google Scholar were searched for English‐language studies published from January 2019 through August 2026, with earlier foundational studies included when necessary. Human cohorts, tumor‐tissue studies, glioma models, microbiota‐transfer experiments, and mechanistic investigations were considered. Preclinical evidence supports several plausible pathways, including changes in short‐chain fatty acid availability, microglial and macrophage states, blood‐brain barrier regulation, systemic immunity, and tryptophan‐related signaling. However, many relevant metabolites may originate from microbial, host, immune, or tumor sources. Human studies remain limited and vulnerable to confounding, reverse causation, treatment effects, and geographic variation. Bacterial nucleic acids and bacteria‐associated HLA‐bound peptides have been detected in brain tumors, but these findings do not establish viable colonization or a gut origin. Low microbial biomass also necessitates rigorous contamination control and orthogonal validation. Microbial influences are biologically plausible modifiers of GBM rather than established drivers. Clinical translation requires longitudinal human studies, source‐resolved analyzes, standardized low‐biomass methods, mechanistic validation, and independent replication. No microbiome‐based biomarker or microbiome‐directed therapy is currently validated for routine GBM care or patient stratification in clinical practice.