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This study reveals a pro\u2010metastatic role for alpha\u20101 antitrypsin (A1AT) in CRC liver metastasis via a dual mechanism involving neutrophil extracellular traps (NETs) and the transmembrane protein coiled\u2010coil domain\u2010containing protein 25 (CCDC25). We demonstrate that A1AT, highly expressed by a liver\u2010metastatic CRC cell line established in a mouse model, directly induces NETs\u2019 formation. Simultaneously, intracellular A1AT binds to CCDC25, preventing its lysosomal degradation and thereby increasing its surface expression. This A1AT\u2010mediated upregulation of CCDC25 sensitizes tumor cells to surrounding NET\u2013DNA. Upon engagement, the ILK\u2013RAC1\u2013CDC42 signaling cascade activates, driving extensive cytoskeletal rearrangement and enhancing the migratory and invasive capabilities of CRC cells. Collectively, our findings elucidate a mechanism wherein tumor cells exploit the A1AT\u2013NET\u2013CCDC25 axis to manipulate neutrophil function and boost metastatic potential. This axis represents a critical driver of CRC liver metastasis, offering novel biomarkers and promising therapeutic targets.<\/jats:p>","DOI":"10.1002\/advs.202520000","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T19:36:12Z","timestamp":1776195372000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor\u2010Derived Alpha\u20101 Antitrypsin Promotes Liver Metastasis of Colorectal Cancer Through the Neutrophil Extracellular Traps\u2013CCDC25 Pathway"],"prefix":"10.1002","volume":"13","author":[{"given":"Qian","family":"Fei","sequence":"first","affiliation":[{"name":"Medical Oncology Department of Gastrointestinal Tumors Liaoning Key Laboratory of Gastrointestinal Cancer Translational Research Cancer Hospital of China Medical University Liaoning Cancer Hospital &amp; Institute Cancer Hospital of Dalian University of Technology  Shenyang China"},{"name":"Department of Oncology 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