Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer

Nat Commun. 2025 Jan 30;16(1):1183. doi: 10.1038/s41467-025-56420-w.

Abstract

Mechanisms related to tumor evasion from NK cell-mediated immune surveillance remain enigmatic. Dickkopf-1 (DKK1) is a Wnt/β-catenin inhibitor, whose levels correlate with breast cancer progression. We find DKK1 to be expressed by tumor cells and cancer-associated fibroblasts (CAFs) in patient samples and orthotopic breast tumors, and in bone. By using genetic approaches, we find that bone-derived DKK1 contributes to the systemic DKK1 elevation in tumor-bearing female mice, while CAFs contribute to DKK1 at primary tumor site. Systemic and bone-specific DKK1 targeting reduce tumor growth. Intriguingly, deletion of CAF-derived DKK1 also limits breast cancer progression, without affecting its levels in circulation, and regardless of DKK1 expression in the tumor cells. While not directly supporting tumor proliferation, stromal-DKK1 suppresses NK cell activation and cytotoxicity by downregulating AKT/ERK/S6 phosphorylation. Importantly, increased DKK1 levels and reduced cytotoxic NK cells are detected in women with progressive breast cancer. Our findings indicate that DKK1 represents a barrier to anti-tumor immunity through suppression of NK cells.

MeSH terms

  • Animals
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / immunology
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Cancer-Associated Fibroblasts / immunology
  • Cancer-Associated Fibroblasts / metabolism
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic*
  • Female
  • Humans
  • Intercellular Signaling Peptides and Proteins* / genetics
  • Intercellular Signaling Peptides and Proteins* / immunology
  • Intercellular Signaling Peptides and Proteins* / metabolism
  • Killer Cells, Natural* / immunology
  • Killer Cells, Natural* / metabolism
  • Mice
  • Mice, Knockout

Substances

  • Intercellular Signaling Peptides and Proteins
  • DKK1 protein, human
  • Dkk1 protein, mouse