转移导致结直肠癌（CRC）的高死亡率。中性粒细胞胞外陷阱（NET）形成增加是转移的主要原因之一。然而，NETs介导的转移机制仍不清楚，也缺乏有效的治疗方法。在这项研究中，我们发现 CRC 患者的中性粒细胞具有增强的 NET 形成能力，并且 NET 的增加与 CRC 进展呈正相关。通过对临床样本和细胞系的定量蛋白质组学分析，我们发现富含半胱氨酸的酸性分泌蛋白（SPARC）减少导致大量NETs形成，而整合素α5β1是NETs与肿瘤细胞相互作用的枢纽蛋白。从机制上讲，SPARC 通过与激活的 C 激酶 1 (RACK1) 受体相互作用来调节烟酰胺腺嘌呤二核苷酸磷酸氧化酶 (NADPH 氧化酶) 途径的激活。过度激活的 NADPH 氧化酶会产生更多的活性氧 (ROS)，从而导致 NET 的释放。然后，NETs上调肿瘤细胞中整合素α5β1的表达，从而增强粘附并激活下游信号通路以促进增殖和迁移。 NADPH 氧化酶抑制剂二亚苯基氯化铵 (DPI) 和整合素 α5β1 抑制剂 ATN-161 (Ac-PHSCN-NH2) 的组合可有效抑制体内肿瘤进展。我们的工作揭示了 NET 与肿瘤进展之间的机制联系，并提出了针对 NET 介导的 CRC 转移的联合疗法。

Metastasis leads to a high mortality rate in colorectal cancer (CRC). Increased neutrophil extracellular traps (NETs) formation is one of the main causes of metastasis. However, the mechanism of NETs-mediated metastasis remains unclear and effective treatments are lacking. In this study, we found neutrophils from CRC patients have enhanced NETs formation capacity and increased NETs positively correlate with CRC progression. By quantitative proteomic analysis of clinical samples and cell lines, we found that decreased secreted protein acidic and rich in cysteine (SPARC) results in massive NETs formation and integrin α5β1 is the hub protein of NETs-tumor cell interaction. Mechanistically, SPARC regulates the activation of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) pathway by interacting with the receptor for activated C kinase 1 (RACK1). Over-activated NADPH oxidase generates more reactive oxygen species (ROS), leading to the release of NETs. Then, NETs upregulate the expression of integrin α5β1 in tumor cells, which enhances adhesion and activates the downstream signaling pathways to promote proliferation and migration. The combination of NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) and integrin α5β1 inhibitor ATN-161 (Ac-PHSCN-NH2) effectively suppresses tumor progression in vivo. Our work reveals the mechanistic link between NETs and tumor progression and suggests a combination therapy against NETs-mediated metastasis for CRC.