Tumor‐Derived Alpha‐1 Antitrypsin Promotes Liver Metastasis of Colorectal Cancer Through the Neutrophil Extracellular Traps–CCDC25 Pathway

ABSTRACT Liver metastasis is a leading cause of mortality in colorectal cancer (CRC), where the inflammatory tumor microenvironment, specifically neutrophil infiltration, significantly promotes metastatic colonization. This study reveals a pro‐metastatic role for alpha‐1 antitrypsin (A1AT) in CRC liver metastasis via a dual mechanism involving neutrophil extracellular traps (NETs) and the transmembrane protein coiled‐coil domain‐containing protein 25 (CCDC25). We demonstrate that A1AT, highly expressed by a liver‐metastatic CRC cell line established in a mouse model, directly induces NETs’ formation. Simultaneously, intracellular A1AT binds to CCDC25, preventing its lysosomal degradation and thereby increasing its surface expression. This A1AT‐mediated upregulation of CCDC25 sensitizes tumor cells to surrounding NET–DNA. Upon engagement, the ILK–RAC1–CDC42 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–NET–CCDC25 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.