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We propose that tumor\u2010initiating cells (TICs) hijack this developmental circuitry to sustain their growth and establish an early immunosuppressive microenvironment during malignant progression. Recent work implicates CXCR4\n                    <jats:sup>+<\/jats:sup>\n                    tissue\u2010resident macrophages (TRMs) in the mammary gland as a central orchestrator of this process. Conserved CXCL12\/CXCR4\u2010AKT\u2010\u03b2\u2010catenin signaling links CXCR4\n                    <jats:sup>+<\/jats:sup>\n                    TRM support of normal mammary stem cells to TIC maintenance, underscoring how developmental niches are exploited in malignancy. During tumorigenesis, aberrant CXCL12 production from tumor\u2010associated fibroblasts promotes the expansion of CXCR4\n                    <jats:sup>+<\/jats:sup>\n                    TRMs, while CXCR4 signaling enhances ALDH1A2\u2010dependent retinoic acid production, which induces regulatory T cells and thereby suppresses anti\u2010tumor immunity at the earliest stages of tumor development. From this perspective, early immune evasion is not only a hallmark of cancer but also a therapeutic window. Targeting TRMs early in cancer development could delay, or even prevent, malignant initiation. More broadly, we propose that TIC\u2013niche crosstalk constitutes a tractable vulnerability, and that incorporating TRM\u2010directed interventions alongside conventional and immune\u2010based therapies may shift the balance toward durable tumor control.\n                  <\/jats:p>","DOI":"10.1002\/bies.70108","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T04:48:43Z","timestamp":1770007723000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophages in the Mammary Gland Stem Cell Niche: A Double\u2010Edged Sword in Tissue Regeneration and Tumor Initiation"],"prefix":"10.1002","volume":"48","author":[{"given":"Eunmi","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Molecular Biology Princeton University  Princeton New Jersey USA"},{"name":"Ludwig Institute for Cancer Research Princeton Branch  Princeton New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yibin","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology Princeton University  Princeton New Jersey USA"},{"name":"Ludwig Institute for Cancer Research Princeton Branch  Princeton New Jersey USA"},{"name":"Cancer Metabolism and Growth Program Rutgers Cancer Institute of New Jersey  New Brunswick New Jersey 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