Chronic stress promotes hepatic immune remodeling through glucocorticoid-driven neutrophil extracellular trap formation in gastric cancer liver metastasis.

Chronic psychological stress is increasingly recognized as an important host-related determinant of cancer progression, yet how stress-associated neuroendocrine signaling reshapes the metastatic immune microenvironment remains incompletely understood. Here, using male mouse models of chronic restraint stress and chronic unpredictable mild stress, together with transcriptomic profiling, flow cytometry, functional assays, and a prospective clinical cohort, we investigated whether chronic stress promotes gastric cancer liver metastasis through glucocorticoid-associated neutrophil reprogramming, neutrophil extracellular trap (NET) formation, and hepatic immune remodeling. Chronic stress induced robust behavioral stress phenotypes, elevated corticosterone levels, and increased hepatic metastatic burden. Immune profiling revealed a myeloid-skewed and immunosuppressive hepatic niche characterized by neutrophil accumulation, impaired CD8+ T-cell effector function, and enhanced T-cell exhaustion. Mechanistically, glucocorticoids activated neutrophils through glucocorticoid receptor signaling, increased reactive oxygen species, and promoted NET formation, whereas pharmacological inhibition of glucocorticoid receptor signaling, degradation of NETs, or antibody-mediated neutrophil depletion attenuated stress-associated metastatic progression in vivo. In parallel, glucocorticoid stimulation increased hepatic lipocalin 2 (LCN2) expression and secretion, and conditioned medium from glucocorticoid-treated hepatocytes enhanced neutrophil migration, an effect attenuated by pharmacological LCN2 inhibition. In vivo, LCN2 blockade reduced circulating LCN2 levels and alleviated hepatic metastatic burden. In patients with gastric cancer liver metastasis, higher stress burden was associated with elevated cortisol and circulating myeloperoxidase-DNA levels and with shorter progression-free survival. Multivariable Cox regression further supported an association between Perceived Stress Scale-defined stress burden and shorter progression-free survival. Together, these findings support a stress-associated glucocorticoid-neutrophil-hepatic niche axis linking chronic stress to metastatic progression.