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Recent data implicate proinflammatory macrophages in the progression of pancreatic ductal adenocarcinoma (PDAC) and its therapeutic response. However, whether or which of the proinflammatory macrophage subtypes play a crucial role in the immune escape of PDAC remains unclear. Here, we identify a population of CD138\n                    <jats:sup>+<\/jats:sup>\n                    tumor-associated macrophages (TAMs), characterized by their proinflammatory and neutrophil-chemotactic activity, which undergo significant expansion in both patients with PDAC and mouse models. These cells are elicited by a local synergy between IL-34\/syndecan-1 and PGE\n                    <jats:sub>2<\/jats:sub>\n                    \/EP2 signaling and are associated with immune evasion and poor clinical outcomes in patients, while also promoting immune escape and disease progression in mouse models. Mechanistically, CD138\n                    <jats:sup>+<\/jats:sup>\n                    TAMs establish a feed-forward loop with immunosuppressive Siglec-F\n                    <jats:sup>+<\/jats:sup>\n                    neutrophils, which exhibit elevated PGE\n                    <jats:sub>2<\/jats:sub>\n                    expression, via the secretion of SAA3 and CXCL1. Targeting CD138\n                    <jats:sup>+<\/jats:sup>\n                    TAMs by disrupting IL-34\/syndecan-1 signaling with anti\u2013IL-34 neutralizing antibodies significantly suppressed PDAC progression, especially when combined with anti\u2013PD-1 antibodies. Together, our study elucidates a CD138\n                    <jats:sup>+<\/jats:sup>\n                    TAM\/Siglec-F\n                    <jats:sup>+<\/jats:sup>\n                    neutrophil axis that drives immune escape in PDAC and proposes a therapeutic strategy that integrates IL-34\/syndecan-1 signaling blockade with anti\u2013PD-1 immunotherapy for the treatment of PDAC.\n                  <\/jats:p>","DOI":"10.1172\/jci199516","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T17:34:31Z","timestamp":1773336871000},"source":"Crossref","is-referenced-by-count":2,"title":["A CD138+ tumor-associated macrophage\/Siglec-F+ neutrophil feed-forward loop promotes immune evasion in pancreatic cancer"],"prefix":"10.1172","volume":"136","author":[{"given":"Chao","family":"Wang","sequence":"first","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Pancreatic Disease,"},{"name":"Department of Hepatobiliary and Pancreatic Surgery, 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