AbstractBackgroundDistant metastasis is a sign of poor prognosis for cancer patients. Extrahepatic liver cancer metastases commonly spread to the lung. Remodelling of the metastatic microenvironment is essential for tumour metastasis. Neutrophil‐associated metastatic microenvironment contributes to the early metastatic colonisation of cancer cells in the lung.MethodThe lung metastasis models were constructed via treated cancer cells by tail vein injection into mice. And samples of lung were harvested at the indicated time to analyze tumor growth and immune cells in the microenvironment. Tumors and lung metastasis specimens were obtained via surgical operations for research purposes. Neutrophils were obtained from peripheral blood of patients with liver cancer or healthy donors (HD).ResultsHepatocellular carcinoma cells reduce the secretion of histidine‐rich glycoprotein (HRG), regulate the recruitment and activation of neutrophils in the metastatic microenvironment and promote the production of neutrophil extracellular traps (NETs), thereby promoting liver cancer lung metastasis. HRG binds to FCγR1 on the neutrophil membrane while inhibiting PI3K and NF‐κB activation, thereby reducing IL‐8 secretion to reduce neutrophil recruitment. Meanwhile, HRG inhibited IL8‐MAPK and NF‐κB pathway activation and ROS production, resulting in reduced NETs formation.ConclusionsOur study reveals that liver cancer regulates neutrophil recruitment and NETs formation in the metastatic microenvironment by reducing HRG secretion, thereby promoting tumour lung metastasis. The results of this study will contribute to the development of possible strategies for treating metastases.