Neutrophil extracellular traps promote liver metastasis by impairing NK cell-dependent tumor surveillance via CCDC25

Tumor metastasis requires constant crosstalk between primary tumor cells and immune cells in distant organs, yet how this interaction shapes the evolving immune landscape of metastatic sites remains unclear. Here, using longitudinal single-cell RNA sequencing in a 4T1 orthotopic breast cancer model, we observe a progressive infiltration of neutrophils, robust NETosis and an immunosuppressive niche during metastatic progression in the liver. Through multiple in vivo models, we determine that macrophage-dependent neutrophil extracellular trap (NET) formation serves as a potent driver of liver metastasis. Mechanistically, extracellular NET-derived DNA is sensed by the transmembrane protein coiled-coil domain containing 25 (CCDC25) on natural killer (NK) cells, and the NET-CCDC25 interaction impairs NK cell surveillance by downregulating multiple activating receptors, including NKG2D, NKp46, NKp44, via the CCDC25-ILK-STAT3 axis. In clinical metastatic liver samples, a higher level of NET expression is associated with NK cell dysfunction. Overall, our findings identify CCDC25 as a potential “innate immune checkpoint” on NK cells, revealing a promising therapeutic strategy to reactivate NK cell function to inhibit liver metastasis. The formation of neutrophil extracellular traps (NETs) contributes to liver metastasis and immune suppression. Here the authors show that NET-derived DNA can be sensed by CCDC25 on natural killer (NK) cells impairing NK cell-dependent tumor surveillance and promoting liver metastasis.