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Here, it dissects the molecular mechanisms underlying NK cell dysfunction in cutaneous malignancies and identifies a paradoxical cytokine shift in tumor\u2010associated NK cells\u2013reduced production of IFN\u2010\u03b3 and TNF\u2010\u03b1 alongside elevated amphiregulin (AREG), an EGFR ligand linked to tumor progression. Single\u2010cell transcriptomic analysis indicates that this reprogramming correlates with elevated glucocorticoid receptor (GR\/NR3C1) pathway activity in tumor\u2010infiltrating NK cells. Functional validation demonstrated that glucocorticoids specifically induce AREG production in NK cells, with tumor\u2010associated prostaglandin E2 (PGE2) augmenting this response. Genetic ablation or pharmacological inhibition of NR3C1 abolished glucocorticoid\u2010driven 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\u2010mediated tumor apoptosis, while the adoptive transfer of AREG\u2010deficient human NK cells significantly suppressed melanoma, cutaneous squamous cell carcinoma (cSCC), and hepatocellular carcinoma growth in NCG mice. These findings establish the GR\u2010AREG axis as a multi\u2010layered therapeutic target for restoring NK cell anti\u2010tumor function.<\/jats:p>","DOI":"10.1002\/advs.202512620","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T03:18:46Z","timestamp":1760411926000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Glucocorticoid Receptor Activation Reprograms NK Cells to Drive AREG\u2010Mediated Immunosuppression: A Pan\u2010Cancer Role for AREG"],"prefix":"10.1002","volume":"13","author":[{"given":"Qin","family":"Wei","sequence":"first","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Dermatology Hospital for Skin Diseases Institute of Dermatology Chinese Academy of Medical Sciences and Peking Union Medical College  Nanjing 210042 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