Chemotherapy Reawakens Dormant Disseminated Pancreatic Cancer Cells in the Liver by Promoting Senescent Hepatocyte-Induced Neutrophil Extracellular Traps

Abstract Chemotherapy remains a cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), yet it paradoxically promotes metastatic recurrence. Elucidation of the underlying mechanisms mediating chemotherapy-induced metastasis could help identify improved combination treatment strategies. Here, we used a dormancy-tracking system to show that chemotherapy awakens dormant disseminated tumor cells (DTCs) in the liver by inducing hepatocyte senescence and subsequent neutrophil extracellular trap (NET) formation. In human and mouse cohorts, adjuvant and neoadjuvant chemotherapy triggered hepatocyte senescence, leading to TGF-β secretion and SMAD-dependent NETosis. NET-derived DNA engaged the transmembrane receptor CCDC25 on dormant DTCs, activating PI3K–AKT signaling and reprogramming DTCs toward a lipid-laden, proliferative phenotype. Genetic or pharmacologic disruption of NET formation, TGF-β signaling, or CCDC25 function effectively suppressed DTC reactivation and hepatic metastasis without compromising chemotherapy efficacy. Clinically, elevated serum NET-DNA levels correlated with hepatocyte senescence, DTC proliferation, and poor survival in PDAC and other solid tumors. Taken together, these findings unveil a senescence–NET–CCDC25 axis that links chemotherapy-induced tissue damage to metastatic relapse, providing a mechanistic basis for adjuvant and neoadjuvant strategies targeting NETosis and CCDC25 to prevent recurrence in PDAC.