Dexamethasone promotes neutrophil ROS-mediated tumor killing through the glucocorticoid receptor

Glucocorticoids are frequently administered to alleviate therapy-related side effects in cancer patients, yet their role in tumor progression remains controversial and mechanistically unresolved. Here, we demonstrate that the long-acting glucocorticoid dexamethasone (Dex) exerts antitumor effects that are mediated by neutrophils. In murine models of Lewis lung carcinoma (LLC) and B16F10 melanoma, Dex markedly suppressed tumor growth and prolonged survival of tumor-bearing mice. These effects were independent of adaptive immunity, macrophages, and tumor cell-intrinsic glucocorticoid signaling, but required functional glucocorticoid receptor (GR) signaling in neutrophils. Dex-treated neutrophils exhibited longer survival and higher cytotoxicity toward tumor cells via increased production of reactive oxygen species (ROS). Disruption of this GR-ROS axis, either through neutrophil-specific GR deletion or pharmacological inhibition of ROS, abolished the antitumor activity of Dex. Together, these findings uncover a neutrophil-mediated tumoricidal function of Dex and suggest that neutrophil GR-ROS signaling may be harnessed for cancer therapy.