Microbiome and pancreatic ductal adenocarcinoma: mechanistic insights, microenvironmental interactions, and therapeutic implications.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by late diagnosis, rapid progression, therapeutic resistance, and a highly immunosuppressive tumor microenvironment (TME). Increasing evidence indicates that the microbiome represents an additional layer of host-tumor interaction influencing PDAC development, progression, and treatment response. PDAC-associated dysbiosis involves coordinated alterations across gut, oral, and intratumoral microbial communities, accompanied by functional changes in microbial metabolism and host signaling. Among microbial groups implicated in PDAC, Firmicutes-associated taxa have attracted particular attention because of their metabolic capacity, including short-chain fatty acid (SCFA) production, and their roles in immune regulation and epithelial homeostasis. Microbiota-derived metabolites may exert context-dependent effects on immune remodeling, metabolic reprogramming, stromal regulation, and TME interactions, with potentially tumor-promoting or tumor-suppressive effects. Meanwhile, microbial signatures and metabolite-associated features are being explored as potential diagnostic, prognostic, and predictive biomarkers. Preclinical studies suggest that microbiome-modulating strategies, including ecological restoration, probiotics, fecal microbiota transplantation, and metabolite-based interventions, may influence therapeutic responsiveness. However, current evidence remains largely observational or preclinical, with unresolved challenges involving causality, reproducibility, methodological standardization, and clinical translation. This review summarizes current knowledge of microbiome-pancreas interactions in PDAC, emphasizing Firmicutes-associated microbial functions, immunometabolic mechanisms, biomarker potential, therapeutic implications, and future directions toward microbiome-informed precision strategies.