Molecular mechanisms by which the intratumoral microbiome drives pancreatic ductal adenocarcinoma progression and therapeutic response
- 1Gansu University of Chinese Medicine
- 2Affiliated Hospital of Gansu University of Chinese Medicine
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.
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BibTeX
@article{qi2026molecular,
title = {{Molecular mechanisms by which the intratumoral microbiome drives pancreatic ductal adenocarcinoma progression and therapeutic response}},
author = {Zhonghua Qi and Miaolei Wang and Yajing Li and Lina Tian and Junhong Liu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1970900},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1970900/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Molecular mechanisms by which the intratumoral microbiome drives pancreatic ductal adenocarcinoma progression and therapeutic response
AU - Zhonghua Qi
AU - Miaolei Wang
AU - Yajing Li
AU - Lina Tian
AU - Junhong Liu
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1970900
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1970900/full
AB - 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.
SN - 1664-3224
ER -