From Microbiome Modulation to Novel Therapeutics: Recent Advances in Therapeutic Strategies for Gastrointestinal Cancers

The gut microbiome has emerged as a key modulator of therapeutic responses in gastrointestinal cancers. This narrative review critically summarizes how specific pathogenic bacteria—including Fusobacterium nucleatum, Bacteroides fragilis, and Gammaproteobacteria—have been implicated in chemoresistance through autophagy activation, suppression of endoplasmic reticulum stress-mediated cell death, inhibition of pyroptosis, induction of cancer-cell quiescence, and direct drug metabolism. In immunotherapy, the microbiome profoundly influences immune checkpoint inhibitor efficacy; Akkermansia muciniphila and Clostridium butyricum enhance anti-tumor immunity via the cGAS-STING pathway and the secD/GRP78/IL-6 axis, while microbial metabolites such as succinate, 4-hydroxyphenylacetic acid, and spatially depleted butyrate promote resistance through CD8+ T-cell exhaustion and immunosuppressive cell recruitment. In gastric cancer, Helicobacter pylori and non-Helicobacter gastric microbiota shape chemotherapy and immunotherapy responses; in hepatocellular carcinoma, the gut–liver axis and bile acid metabolism influence immune checkpoint blockade; and in pancreatic ductal adenocarcinoma, intratumoral Gammaproteobacteria and metabolites such as trimethylamine N-oxide and indole-3-acetic acid modulate gemcitabine resistance and immunotherapy efficacy. We further evaluate emerging microbiome-targeted strategies including fecal microbiota transplantation, engineered probiotics, and bacteriophage therapy, and discuss challenges in clinical translation. By elucidating the molecular mechanisms of microbiome-mediated therapy modulation, we propose a hypothesis-generating, evidence-graded framework for future prospective validation in microbiome-guided precision oncology.