Microbiome-pancreatic cancer crosstalk: From tumor biology to therapeutic intervention.

Pancreatic cancer (PC) remains one of the most lethal malignancies worldwide, characterized by dense desmoplastic stroma, profound immunosuppression, and poor responsiveness to conventional therapies. Accumulating evidence positions the intratumoral microbiome, encompassing bacteria as well as understudied fungal and viral components, as a critical regulator of PC pathogenesis, tumor microenvironment (TME) remodeling, and therapeutic efficacy. In this review, we synthesize the current understanding of the pancreatic intratumoral microbiome, including its distinct composition relative to normal pancreatic tissue, gut microbiota, and oral microbiota. The PC intratumoral microbiome is characterized by enrichment of validated pro-tumorigenic drivers (e.g., Pseudomonas, Bacteroides species) alongside protective taxa (e.g., Lactobacillus species). These taxonomic profiles vary significantly based on disease stage, patient demographics, and treatment history. We dissected the mechanisms by which microbes and their derivatives drive PC initiation and progression, including immune suppression through modulation of myeloid-derived suppressor cells and regulatory T cells, metabolic reprogramming involving short-chain fatty acids and the tryptophan metabolite 3-indoleacetic acid (3-IAA), and stromal remodeling via activation of cancer-associated fibroblasts. The influence of the microbiome on therapeutic response is examined, with particular emphasis on microbial-mediated mechanisms that undermine treatment efficacy. We further summarize diagnostic and prognostic biomarkers, including salivary microbial signatures with moderate sensitivity and specificity, circulating microbial DNA, and composite microbial risk scores that integrate multiple bacterial species to predict survival. Therapeutic strategies targeting the microbiome are discussed, distinguishing clinically translatable approaches from experimental concepts requiring further validation. Finally, we outline challenges in standardizing profiling methods, validating microbial signatures across diverse populations, and translating preclinical insights to clinical practice, emphasizing the need for multi-omics integration and interdisciplinary collaboration to advance microbiome-driven PC management.