CXCR4+ mammary gland macrophageal niche promotes tumor initiating cell activity and immune suppression during tumorigenesis

Eunmi Lee, Jason J. Hong, Gabriel Samcam Vargas, Natalie Sauerwald, Yong Wei, Xiang Hang, Chandra L. Theesfeld, Jean Arly A. Volmar, Jennifer M. Miller, Wei Wang, Sha Wang, Gary Laevsky, Christina J. DeCoste and Yibin Kang ()
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Eunmi Lee: Princeton University
Jason J. Hong: Princeton University
Gabriel Samcam Vargas: Princeton University
Natalie Sauerwald: Flatiron Institute
Yong Wei: Princeton University
Xiang Hang: Princeton University
Chandra L. Theesfeld: Princeton University
Jean Arly A. Volmar: Princeton University
Jennifer M. Miller: Princeton University
Wei Wang: Princeton University
Sha Wang: Princeton University
Gary Laevsky: Princeton University
Christina J. DeCoste: Princeton University
Yibin Kang: Princeton University

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: Abstract Tumor-initiating cells (TICs) share features and regulatory pathways with normal stem cells, yet how the stem cell niche contributes to tumorigenesis remains unclear. Here, we identify CXCR4+ macrophages as a niche population enriched in normal mammary ducts, where they promote the regenerative activity of basal cells in response to luminal cell-derived CXCL12. CXCL12 triggers AKT-mediated stabilization of β-catenin, which induces Wnt ligands and pro-migratory genes, enabling intraductal macrophage infiltration and supporting regenerative activity of basal cells. Notably, these same CXCR4+ niche macrophages regulate the tumor-initiating activity of various breast cancer subtypes by enhancing TIC survival and tumor-forming capacity, while promoting early immune evasion through regulatory T cell induction. Furthermore, a CXCR4+ niche macrophage gene signature correlates with poor prognosis in human breast cancer. These findings highlight the pivotal role of the CXCL12-CXCR4 axis in orchestrating interactions between niche macrophages, mammary epithelial cells, and immune cells, thereby establishing a supportive niche for both normal tissue regeneration and mammary tumor initiation.

Date: 2025
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DOI: 10.1038/s41467-025-59972-z

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