Glucocorticoid Receptor Activation Reprograms NK Cells to Drive AREG-Mediated Immunosuppression: A Pan-Cancer Role for AREG.

ABSTRACT: Natural killer (NK) cells are potent mediators of anti-tumor immunity, yet their functions are frequently subverted by tumor microenvironment-driven immunosuppression. Here, it dissects the molecular mechanisms underlying NK cell dysfunction in cutaneous malignancies and identifies 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) augment

SUBMITTER: Wei Q 

PROVIDER: S-EPMC12786305 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature