Immune checkpoint inhibitors (ICIs) have changed systemic therapy for advanced gastric cancer and gastroesophageal junction cancer, but both primary and acquired resistance remain frequent. This narrative review synthesizes clinical and translational evidence focused on how the tumor microenvironment (TME), host immune factors, and the gut microbiome interact to shape ICI resistance in gastric cancer. The authors prioritized gastric cancer–specific studies and supplemented this with systematic reviews, meta-analyses, and mechanistically relevant data from other tumor types when gastric cancer evidence was limited.
The review used a structured PubMed search through 28 August 2026. Gastric cancer–specific clinical and translational evidence was emphasized; where necessary, findings from other cancers and broader microbiome or TME studies were included to provide mechanistic context. The authors note that much of the human microbiome literature is retrospective, cross-sectional, or derived from non-gastric cancer cohorts, which affects the strength of causal inference.
Within the gastric cancer TME, multiple cellular and structural components can promote immune exclusion or dysfunction. Key elements described in the review include cancer-associated fibroblasts, diverse myeloid cell populations, regulatory T cells, and mechanisms that remodel the extracellular matrix. Microenvironmental features such as hypoxia, angiogenesis, and chronic antigen exposure that leads to T-cell exhaustion are also implicated. Together, these TME characteristics may limit immune cell infiltration or impair effector T-cell function, undermining the efficacy of ICIs despite currently used tumor biomarkers.
The gut microbiome is presented as a modulator of systemic immune responses with potential to affect ICI outcomes. Factors highlighted include microbial diversity, specific microbial metabolites, and exposures that alter gut communities such as antibiotics and proton pump inhibitors (PPIs). Interventions that directly modify the microbiome—defined live biotherapeutics, fecal microbiota transplantation (FMT), and diet—are discussed as biologically plausible modulators of antitumor immunity. However, the review emphasizes that most human evidence linking the gut microbiome to ICI response in gastric cancer is limited in design and often extrapolated from other tumor types.
Based on the available evidence, the authors recommend several pragmatic, supportive clinical measures rather than empiric microbiome-targeted anticancer therapies. Reasonable actions include antibiotic stewardship to avoid unnecessary disruption of gut microbial communities, reassessment of unneeded acid suppression (PPIs), and nutritional optimization for patients undergoing ICI therapy. These measures are framed as precautionary and supportive, aligning with the limited and predominantly observational evidence base.
The review identifies several microbiome-directed approaches that remain investigational in gastric cancer. Routine probiotic supplementation is not currently supported. Specific interventions such as Clostridium butyricum MIYAIRI 588 proposed for ICI sensitization and fecal microbiota transplantation have insufficient evidence in gastric cancer to warrant routine clinical use. The authors explicitly classify these strategies as experimental, indicating that they should be evaluated in controlled clinical studies before adoption.
The review outlines key methodological needs for future studies to clarify causality and identify actionable biomarkers. Recommended elements include longitudinally captured exposure data, serial profiling of the TME, stool metagenomic analysis, detailed records of medication use (including antibiotics and PPIs), assessment of nutritional status, and correlation with clinical outcomes. Integrating these data streams may enable biomarker-guided research into the TME–gut microbiome axis and support development of targeted interventions to overcome ICI resistance.
The TME–gut microbiome axis offers a biologically plausible framework to explain and investigate immunotherapy resistance in gastric cancer. While mechanistic rationale and some associative evidence exist, current human data are largely observational or derived from other cancers. Consequently, empiric microbiome-directed anticancer therapy in gastric cancer is not justified at present. Clinicians may consider antibiotic stewardship, careful evaluation of acid suppression, and nutritional optimization as supportive measures while awaiting prospective, longitudinal studies integrating TME profiling, stool metagenomics, medication exposure, nutrition, and clinical outcomes.