Glucocorticoid receptor activation reprograms NK cells to drive AREG-mediated immunosuppression in skin cancer

Summary Natural killer (NK) cells are potent mediators of anti-tumor immunity, yet their functions are frequently subverted by tumor microenvironment-driven immunosuppression. Here, we dissect the molecular mechanisms underlying NK cell dysfunction in cutaneous malignancies and identify a paradoxical cytokine shift in tumor-associated NK cells-reduced production of IFN-γ and TNF-α alongside elevated amphiregulin (AREG), an EGFR ligand linked to tumor progression. Single-cell transcriptomic analysis indicates that this reprogramming correlates with elevated glucocorticoid receptor (GR/NR3C1) pathway activity in tumor-infiltrating NK cells. Functional validation demonstrated that glucocorticoids specifically induce AREG production in NK cells, with tumor-associated prostaglandin E2 (PGE2) augmenting this response. Genetic ablation or pharmacological inhibition of NR3C1 abolished glucocorticoid-driven AREG induction. Moreover, primary GR activation established persistent chromatin accessibility at the AREG locus, sensitizing NK cells to enhanced AREG production upon secondary glucocorticoid exposure. Functionally, AREG counteracts NK cell-mediated tumor apoptosis, while adoptive transfer of AREG-deficient human NK cells significantly suppressed melanoma, cutaneous squamous cell carcinoma (cSCC), and hepatocellular carcinoma growth in NCG mice. These findings establish the GR-AREG axis as a multi-layered therapeutic target for restoring NK cell anti-tumor function. Graphical abstract