Microbiota and infection-driven mechanisms in upper gastrointestinal malignancies

The human microbiota - comprising bacteria, fungi, archaea, and viruses - forms a complex ecosystem that maintains host homeostasis through multifaceted host-microbe interactions. Increasing evidence suggests associations between microbial dysbiosis and upper gastrointestinal malignancies, including esophageal cancer, gastric cancer, pancreatic cancer, and hepatocellular carcinoma. Mechanistically, tumor-associated microbes may contribute to carcinogenesis through several convergent pathways, including direct genotoxicity, activation of oncogenic signaling cascades such as TLR/NF-κB pathway, induction of chronic inflammation, metabolic reprogramming and modulation of anti-tumor immunity. Key tumor-associated microbiota - Fusobacterium nucleatum, Porphyromonas gingivalis, Helicobacter pylori, and hepatitis B virus- exhibit cancer-type-specific enrichment patterns and are associated with clinicopathological features and prognosis. This review synthesizes current evidence on microbiota-driven mechanisms in upper gastrointestinal cancers, critically evaluates the strength of evidence for each microbe-cancer relationship, and explores the translational potential of microbiota-based biomarkers for early detection and prognosis. However, most current evidence remains limitations, and large-scale prospective studies with standardized methodologies are needed to establish causality and enable clinical translation.