Molecular mechanisms by which the intratumoral microbiome drives pancreatic ductal adenocarcinoma progression and therapeutic response
Year: 2026
Type: review
Abstract: Pancreatic ductal adenocarcinoma has an extremely poor prognosis. Pancreatic ductal adenocarcinoma harbors a multidomain intratumoral microbial community dominated by bacteria and also containing fungi; its composition differs fundamentally from that of normal pancreatic tissue and drives malignant progression through three major axes: inflammatory-immune signaling, metabolic-epigenetic regulation, and stromal remodeling. Gammaproteobacterial lipopolysaccharide establishes a chronic proinflammatory microenvironment through the Toll-like receptor 4-nuclear factor kappa B axis, whereas in situ gemcitabine inactivation by the long isoform of bacterial cytidine deaminase represents the best-supported microbiome-mediated mechanism of drug resistance to date. In experimental systems, Fusobacterium nucleatum has been linked to tumor-cell invasion and alternatively activated macrophage polarization. In mouse and cell models, intratumoral fungi have been implicated in immunosuppressive signaling through the C-type lectin receptor dectin-1-interleukin 33 axis and the mannose-binding lectin-complement pathway; their relevance to human pancreatic ductal adenocarcinoma remains debated. These three axes may converge on stromal activation and epithelial-mesenchymal transition and contribute to invasion and treatment resistance. Antimicrobial strategies targeting drug-resistance-associated bacteria can restore gemcitabine efficacy in animal experiments and have been explored experimentally alongside programmed cell death protein 1 blockade; the clinically appropriate patient populations and optimal sequencing of such combinations remain to be defined in prospective trials.
Source: Frontiers in Immunology
Institution: Gansu University of Traditional Chinese Medicine
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223177440