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Methods:\u00a0Using\u00a0in vitro\u00a0(tumor\u2010DRG co\u2010culture) and\u00a0in vivo\u00a0(sciatic nerve injection) models coupled with protein identification by liquid chromatography\u2010mass spectrometry (LC\u2010MS) and ChIP\u2010seq, the role of steroid receptor coactivator\u20101 (SRC\u20101) is investigated in TAM reprogramming and PNI. SRC\u20101 is up\u2010regulated in TAMs and promotes PNI by binding to signal transducer and activator of transcription 1(STAT1) to enhance\u00a0matrix metallopeptidase 12 (MMP12) transcription. SRC\u20101 knockdown attenuated M2\u2010like characteristics in TAMs, reduced MMP12 secretion, and suppressed PNI. Importantly,\u00a0blocking the SRC\u20101\/STAT1\/MMP12 axis\u00a0(using SRC\u20101\u2010KO TAMs or MMP12 inhibitors) attenuated PNI progression in vivo. SRC\u20101 reprograms TAMs via STAT1\u2010mediated MMP12 activation to facilitate PNI.\u00a0Targeting SRC\u20101 disrupts this axis and presents a novel therapeutic strategy against PNI in pancreatic cancer.<\/jats:p>","DOI":"10.1002\/advs.202416575","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T10:40:59Z","timestamp":1758624059000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Steroid Receptor Coactivator\u20101 Drives Tumor\u2010Associated Macrophage Reprogramming by Mediating MMP12 Transcription in Pancreatic Cancer Perineural Invasion"],"prefix":"10.1002","volume":"12","author":[{"given":"Ke","family":"Cheng","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital Institute of Cancer Stem Cell Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Liu","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital Institute of Cancer Stem Cell Dalian Medical University  Dalian 116044 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education Shanghai Jiao Tong University School of Medicine. 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