Chronic stress contributes to increased incidence of metastasis and poor prognosis in patients with cancer. Although the reasons for this were previously unclear, He et al. now establish that stress induces neutrophil extracellular trap (NET) formation to promote metastasis.

To characterize microenvironmental changes necessary for stress-induced metastasis, the authors performed bulk RNA sequencing and immunofluorescence of the lungs of chronically stressed mice. Lungs from stressed mice had increased fibronectin deposition, reduced T cell infiltration and increased neutrophil infiltration. Co-culture of T cells with neutrophils treated with a glucocorticoid receptor agonist, GSK9027, or a vehicle control, demonstrated that glucocorticoid receptor-activated neutrophils failed to stimulate T cell activation, suggesting that stress inhibits T cell activation through neutrophils. In an experimental lung metastasis mouse model, depletion of neutrophils prevented increased metastasis in stress-exposed mice.