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

Qin Wei1, Guirong Liang1, Rui Zeng1

  • 1Jiangsu Provincial Key Laboratory of Dermatology, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, 210042, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 13, 2025
PubMed

Insights

Natural killer (NK) cells combat tumors but are suppressed in the tumor microenvironment. Glucocorticoid receptor (GR) activation drives amphiregulin (AREG) production, impairing NK cell anti-tumor activity and offering a therapeutic target.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Natural killer (NK) cells are crucial for anti-tumor immunity.
  • Tumor microenvironments often induce immunosuppression, impairing NK cell function.
  • Cutaneous malignancies exhibit NK cell dysfunction characterized by reduced IFN-γ/TNF-α and increased amphiregulin (AREG).

Purpose of the Study:

  • To investigate the molecular mechanisms of NK cell dysfunction in cutaneous malignancies.
  • To identify the role of the glucocorticoid receptor (GR/NR3C1) pathway in reprogramming tumor-associated NK cells.
  • To evaluate the therapeutic potential of targeting the GR-AREG axis.

Main Methods:

  • Single-cell transcriptomic analysis of tumor-infiltrating NK cells.
  • Functional validation of glucocorticoid and prostaglandin E2 (PGE2) effects on NK cells.
  • Genetic ablation and pharmacological inhibition of NR3C1.
  • Assessment of AREG's impact on NK cell-mediated apoptosis.
  • Adoptive transfer of AREG-deficient NK cells in mouse models.

Main Results:

  • Elevated GR/NR3C1 pathway activity correlates with NK cell reprogramming.
  • Glucocorticoids induce AREG production in NK cells, augmented by PGE2.
  • NR3C1 inhibition blocks glucocorticoid-driven AREG induction.
  • GR activation leads to persistent chromatin accessibility at the AREG locus.
  • AREG production impairs NK cell anti-tumor apoptosis; AREG-deficient NK cells suppress tumor growth.

Conclusions:

  • The GR-AREG axis is a key mechanism of NK cell suppression in cancer.
  • Targeting GR or AREG can restore NK cell anti-tumor functions.
  • This axis represents a promising multi-layered therapeutic strategy for enhancing anti-cancer immunity.
Keywords:
AREGGlucocorticoid receptorNK cellsPGE2Tumor microenvironment

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