Gut microbiota modulation of gastrointestinal cancers: from dysbiosis signatures to therapeutic interventions.

The human gut microbiota constitutes the largest and most metabolically active microbial ecosystem in the body, and accumulating evidence links dynamic alterations in microbial composition and function to the initiation, progression, and treatment responses of multiple gastrointestinal (GI) cancers, including esophageal, gastric, hepatocellular, pancreatic, and colorectal malignancies. This review synthesizes current evidence on dysbiosis signatures, mechanistic pathways, and translational opportunities across major GI cancer types, with a focus on microbe-derived metabolites and microbe-associated molecular patterns that shape inflammation, epithelial barrier integrity, and antitumor immunity. Across GI cancers, recurrent patterns include enrichment of pro-inflammatory/pathobiont taxa, depletion of homeostasis-maintaining and butyrate-producing commensals, and perturbations in metabolic axes centered on bile acids and short-chain fatty acids. Mechanistically, these changes can remodel the tumor microenvironment via epithelial and immune signaling, epigenetic regulation, and metabolic reprogramming. Importantly, the gut microbiota is increasingly recognized as a modifiable determinant of the efficacy and toxicity of immune checkpoint blockade, adoptive cell therapies, chemotherapy, and radiotherapy. Despite rapid advances, key challenges persist in translating microbiome research into cancer care, including validation, standardization, variability, and safety. Future success likely depends on function-oriented, targeted modulation, supported by multi-omics, strong causal evidence, and clinical trials.