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

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.