{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:38:55Z","timestamp":1793158735867,"version":"4.5.0"},"reference-count":235,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T00:00:00Z","timestamp":1640908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA194013"],"award-info":[{"award-number":["R01CA194013"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA192064"],"award-info":[{"award-number":["R01CA192064"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM121322"],"award-info":[{"award-number":["P20GM121322"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Despite modest improvements in survival in recent years, pancreatic adenocarcinoma remains a deadly disease with a 5-year survival rate of only 9%. These poor outcomes are driven by failure of early detection, treatment resistance, and propensity for early metastatic spread. Uncovering innovative therapeutic modalities to target the resistance mechanisms that make pancreatic cancer largely incurable are urgently needed. In this review, we discuss the immune composition of pancreatic tumors, including the counterintuitive fact that there is a significant inflammatory immune infiltrate in pancreatic cancer yet anti-tumor mechanisms are subverted and immune behaviors are suppressed. Here, we emphasize how immune cell interactions generate tumor progression and treatment resistance. We narrow in on tumor macrophage (TAM) spatial arrangement, polarity\/function, recruitment, and origin to introduce a concept where interactions with tumor neutrophils (TAN) perpetuate the microenvironment. The sequelae of macrophage and neutrophil activities contributes to tumor remodeling, fibrosis, hypoxia, and progression. We also discuss immune mechanisms driving resistance to standard of care modalities. Finally, we describe a cadre of treatment targets, including those intended to overcome TAM and TAN recruitment and function, to circumvent barriers presented by immune infiltration in pancreatic adenocarcinoma.<\/jats:p>","DOI":"10.3390\/cancers14010194","type":"journal-article","created":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T20:49:38Z","timestamp":1641242978000},"page":"194","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Macrophage and Neutrophil Interactions in the Pancreatic Tumor Microenvironment Drive the Pathogenesis of Pancreatic Cancer"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3058-7434","authenticated-orcid":false,"given":"Hillary G.","family":"Pratt","sequence":"first","affiliation":[{"name":"Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA"},{"name":"WVU Cancer Institute, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2882-8593","authenticated-orcid":false,"given":"Kayla J.","family":"Steinberger","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8220-6613","authenticated-orcid":false,"given":"Nicole E.","family":"Mihalik","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Ott","sequence":"additional","affiliation":[{"name":"Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1375-4189","authenticated-orcid":false,"given":"Thomas","family":"Whalley","sequence":"additional","affiliation":[{"name":"School of Biosciences, Cardiff University, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Szomolay","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity & Systems Immunity Research Institute, Cardiff University, Cardiff CF14 4XN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian A.","family":"Boone","sequence":"additional","affiliation":[{"name":"Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA"},{"name":"WVU Cancer Institute, West Virginia University, Morgantown, WV 26506, USA"},{"name":"Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506, USA"},{"name":"Department of Surgery, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8225-7824","authenticated-orcid":false,"given":"Timothy D.","family":"Eubank","sequence":"additional","affiliation":[{"name":"Cancer Cell Biology, West Virginia University, Morgantown, WV 26506, USA"},{"name":"WVU Cancer Institute, West Virginia University, Morgantown, WV 26506, USA"},{"name":"Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506, USA"},{"name":"The In Vivo Multifunctional Magnetic Resonance Center, West Virginia University, Morgantown, WV 26506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1158\/0008-5472.CAN-14-0155","article-title":"Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States","volume":"74","author":"Rahib","year":"2014","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4846","DOI":"10.3748\/wjg.v24.i43.4846","article-title":"Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes","volume":"24","author":"McGuigan","year":"2018","journal-title":"World J. 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