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

• DOI: 10.1038/s41467-025-56420-w
• Publication Date: 2025-01-30T15:15:44Z
• Authors: Seunghyun Lee; Biancamaria Ricci; Jennifer Tran; Emily Eul; Jiayu Ye; Qihao Ren; David Clever; Julia Wang; Pamela Wong; Michael S. Haas; Sheila A. Stewart; Cynthia X. Ma; Todd A. Fehniger; Roberta Faccio
• Keywords: DKK1; Tumor progression; Cancer-Associated Fibroblasts

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 be expressed by cells and cancer-associated fibroblasts (CAFs) in patient samples orthotopic tumors, bone. By using genetic approaches, we that bone-derived contributes the systemic elevation tumor-bearing female mice, while CAFs contribute at primary site. Systemic bone-specific targeting reduce growth. Intriguingly, deletion of CAF-derived also limits progression, without affecting its circulation, regardless expression cells. While not directly supporting proliferation, stromal-DKK1 suppresses cell activation cytotoxicity downregulating AKT/ERK/S6 phosphorylation. Importantly, increased reduced cytotoxic are detected women progressive cancer. Our findings indicate represents barrier anti-tumor immunity through suppression