Decoding the microbial blueprint of pancreatic cancer

Pancreatic cancer (PC) represents one of the most formidable challenges in oncology, characterized by its asymptomatic onset, delayed clinical detection, and dismal prognosis. Among pancreatic neoplasms, pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of cases and remains the most aggressive form, driven by late diagnosis, intrinsic chemoresistance, and a profoundly immunosuppressive tumor microenvironment. Recent advances have reframed the human microbiome not as a passive bystander but as an active architect of pancreatic tumor biology. This review delineates the mechanistic axes through which microbial ecosystems orchestrate PDAC progression across four key anatomical niches-gastrointestinal, oral, urogenital, and intrapancreatic. We elucidate how microbial dysbiosis fosters oncogenesis through immune evasion, metabolic reprogramming, and chronic inflammation, implicating specific taxa such as Fusobacterium nucleatum , Malassezia spp., and Porphyromonas gingivalis in immune suppression and chemoresistance. Microbial enzymatic inactivation of gemcitabine and modulation of cytokine networks further underscore the microbiome’s pivotal role in therapeutic failure. Conversely, commensal and probiotic species may potentiate immunosurveillance and enhance treatment efficacy. This review also explores microbiota-derived biomarkers for early detection and the translational promise of microbiome-targeted interventions, including fecal microbiota transplantation, probiotics, and selective antibiotics. By decoding the microbial blueprint of PC, we propose a paradigm in which the microbiome emerges as both a biomarker and a therapeutic axis, offering novel avenues for precision oncology. Furthermore, this integrative synthesis emphasizes the multi-omic, immunometabolic, and therapeutic dimensions of the pancreatic cancer-microbiome interface, where metagenomic, transcriptomic, metabolomic, and immunomic layers converge to shape tumor evolution and therapeutic response, advancing the vision of microbiome-informed precision oncology.