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Inspired by the pro\u2010inflammatory M1\u2010like response triggered by trypsinogen in pancreatitis, trypsinogen as a novel macrophage reprogrammer is identified. Here, it is shown that trypsinogen drives M2\u2010to\u2010M1 repolarization via NF\u2010\u03baB activation. To harness this activity, a pancreatitis\u2010inspired nanoplatform (JT@NPs\u2010aCD11b) co\u2010delivering trypsinogen and the CD47 inhibitor JQ1 to TAMs is developed. In pancreatic cancer models, JT@NPs\u2010aCD11b reprogrammed TAMs to an M1 phenotype while JQ1 blocked the \u201cdo not eat me\u201d signal on cancer cells, synergistically enhancing phagocytosis. This strategy remodeled the immunosuppressive microenvironment, increased effector immune cells, and reduced suppressive populations, leading to potent tumor suppression, prolonged survival, and durable immune memory. Macrophage depletion abrogated efficacy, confirming TAMs as the primary mediators. This work establishes trypsinogen as a versatile immunomodulator and its nanoplatform as a promising strategy for pancreatic cancer immunotherapy.<\/jats:p>","DOI":"10.1002\/advs.76386","type":"journal-article","created":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T11:24:03Z","timestamp":1782559443000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Pancreatitis\u2010Inspired Trypsinogen Nanoplatform Reprograms Tumor\u2010Associated Macrophages via NF\u2010\u03baB for Pancreatic Cancer Immunotherapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Lei","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Radiology Sichuan Academy of Medical Sciences Sichuan Provincial People's Hospital University of Electronic Science and Technology of China  Chengdu Sichuan P. R. 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