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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\u2010tumorigenic drivers (e.g.,\n                    <jats:italic>Pseudomonas<\/jats:italic>\n                    ,\n                    <jats:italic>Bacteroides<\/jats:italic>\n                    species) alongside protective taxa (e.g.,\n                    <jats:italic>Lactobacillus<\/jats:italic>\n                    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\u2010derived suppressor cells and regulatory T cells, metabolic reprogramming involving short\u2010chain fatty acids and the tryptophan metabolite 3\u2010indoleacetic acid (3\u2010IAA), and stromal remodeling via activation of cancer\u2010associated fibroblasts. The influence of the microbiome on therapeutic response is examined, with particular emphasis on microbial\u2010mediated 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\u2010omics integration and interdisciplinary collaboration to advance microbiome\u2010driven PC management.\n                  <\/jats:p>","DOI":"10.1002\/imo2.70126","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T07:46:06Z","timestamp":1785311166000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microbiome\u2014pancreatic cancer crosstalk: From tumor biology to therapeutic intervention"],"prefix":"10.1002","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2937-7477","authenticated-orcid":false,"given":"Yuqin","family":"Xie","sequence":"first","affiliation":[{"name":"School of Medicine, Chongqing University Chongqing University Cancer Hospital Chongqing China"},{"name":"Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis Chongqing University Cancer Hospital Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis Chongqing University Cancer Hospital Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis Chongqing University Cancer Hospital Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maoyun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis Chongqing University Cancer Hospital Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4202-9173","authenticated-orcid":false,"given":"Fengsheng","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis Chongqing University Cancer Hospital Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhen","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis Chongqing University Cancer Hospital Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis Chongqing University Cancer Hospital Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athena","family":"Savoji","sequence":"additional","affiliation":[{"name":"Department of Chemical and Physical Sciences University of Toronto Mississauga Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Pancreatic Tumor Center, Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis Chongqing University Cancer Hospital Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip B.","family":"Hylemon","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Virginia Commonwealth University Richmond Virginia USA"},{"name":"Stravitz\u2010Sanyal Institute for Liver Disease &amp; Metabolic Health Virginia Commonwealth University Richmond VA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiping","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology Virginia Commonwealth University Richmond Virginia USA"},{"name":"Stravitz\u2010Sanyal Institute for Liver Disease &amp; Metabolic Health Virginia Commonwealth University Richmond VA USA"},{"name":"Richmond Veteran Affairs Medical Center Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine, Chongqing University 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