Chronic stress increases metastasis in cancer patients by altering the tumor microenvironment, particularly through neutrophil-mediated changes. The study shows that chronic stress significantly increases lung metastasis in mice, with fibronectin accumulation, reduced T cell infiltration, and increased neutrophil infiltration. Depleting neutrophils abolishes stress-induced metastasis, indicating that neutrophils play a key role in this process. Chronic stress shifts the normal circadian rhythm of neutrophils and increases neutrophil extracellular trap (NET) formation via glucocorticoid release. In mice with neutrophil-specific glucocorticoid receptor deletion, chronic stress fails to increase NETs and metastasis. Digesting NETs with deoxyribonuclease (DNase) I prevents chronic stress-induced metastasis, suggesting that NETs are a key factor in the metastatic process. The study reveals that glucocorticoids released during chronic stress cause NET formation and establish a metastasis-promoting microenvironment. Therefore, targeting NETs could be a potential strategy for preventing metastatic recurrence in cancer patients, many of whom experience chronic stress due to their disease. The findings highlight the importance of understanding the role of stress in cancer progression and the potential for therapeutic interventions targeting stress-induced changes in the tumor microenvironment.Chronic stress increases metastasis in cancer patients by altering the tumor microenvironment, particularly through neutrophil-mediated changes. The study shows that chronic stress significantly increases lung metastasis in mice, with fibronectin accumulation, reduced T cell infiltration, and increased neutrophil infiltration. Depleting neutrophils abolishes stress-induced metastasis, indicating that neutrophils play a key role in this process. Chronic stress shifts the normal circadian rhythm of neutrophils and increases neutrophil extracellular trap (NET) formation via glucocorticoid release. In mice with neutrophil-specific glucocorticoid receptor deletion, chronic stress fails to increase NETs and metastasis. Digesting NETs with deoxyribonuclease (DNase) I prevents chronic stress-induced metastasis, suggesting that NETs are a key factor in the metastatic process. The study reveals that glucocorticoids released during chronic stress cause NET formation and establish a metastasis-promoting microenvironment. Therefore, targeting NETs could be a potential strategy for preventing metastatic recurrence in cancer patients, many of whom experience chronic stress due to their disease. The findings highlight the importance of understanding the role of stress in cancer progression and the potential for therapeutic interventions targeting stress-induced changes in the tumor microenvironment.