Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1β (IL-1β) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1β axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.

肺转移是乳腺癌相关死亡的主要原因。中性粒细胞相关的炎症微环境有助于肿瘤细胞在肺部转移定植。在这里，我们展示了肿瘤分泌的蛋白酶组织蛋白酶 C (CTSC) 通过调节中性粒细胞的募集和中性粒细胞胞外陷阱 (NETs) 的形成来促进乳腺到肺的转移。CTSC 酶促激活中性粒细胞膜结合蛋白酶 3 (PR3) 以促进白细胞介素 1β (IL-1β) 加工和核因子 κB 活化，从而上调 IL-6 和 CCL3 以募集中性粒细胞。此外，CTSC-PR3-IL-1β 轴诱导中性粒细胞活性氧的产生和 NET 的形成，从而降解血小板反应蛋白-1 并支持癌细胞在肺部的转移性生长。CTSC 的表达和分泌与人乳腺肿瘤中的 NET 形成和肺转移有关。重要的是，在小鼠模型中，用化合物 AZD7986 靶向 CTSC 可有效抑制乳腺癌的肺转移。总体而言，我们的研究结果揭示了肿瘤细胞如何调节转移性生态位中的中性粒细胞并支持 CTSC 靶向癌症治疗方法的机制。