Tumor microenvironment and gut microbiome in immunotherapy resistance in gastric cancer: clinical questions, biological mechanisms, and evidence-based therapeutic perspectives.

Immune checkpoint inhibitors (ICIs) have improved systemic therapy for advanced gastric and gastroesophageal junction cancer, yet primary and acquired resistance remain common and are incompletely explained by established tumor biomarkers. This narrative review evaluates the connected roles of the tumor microenvironment (TME), host immunity, and the gut microbiome in shaping ICI resistance in gastric cancer. We performed a structured PubMed search through 28 August 2026 and prioritized gastric cancer-specific clinical and translational evidence, supplemented by systematic reviews, meta-analyses, and mechanistically relevant studies from other tumor types when necessary. Within the gastric cancer TME, cancer-associated fibroblasts, myeloid cells, regulatory T cells, extracellular matrix remodeling, hypoxia, angiogenesis, and T-cell exhaustion can promote immune exclusion or dysfunction. Microbial diversity, microbial metabolites, antibiotics, proton pump inhibitors, defined live biotherapeutics, fecal microbiota transplantation, and diet may influence systemic antitumor immunity, but most human evidence is retrospective, cross-sectional, or derived from non-gastric cancers. Clinically, antibiotic stewardship, reassessment of unnecessary acid suppression, and nutritional optimization are reasonable supportive measures, whereas routine probiotic supplementation, Clostridium butyricum MIYAIRI 588 for ICI sensitization, and fecal microbiota transplantation remain investigational in gastric cancer. Future studies should integrate longitudinal exposures, serial TME profiling, stool metagenomics, medication use, nutritional status, and clinical outcomes. The TME-gut microbiome axis is therefore a biologically plausible framework for biomarker-guided research, but current evidence does not justify empiric microbiome-directed anticancer therapy in gastric cancer.