Macrophages in the Mammary Gland Stem Cell Niche: A Double‐Edged Sword in Tissue Regeneration and Tumor Initiation

Stem cell populations employ cell‐intrinsic and niche‐mediated mechanisms to preserve long‐term self‐renewal and regenerative potential. We propose that tumor‐initiating cells (TICs) hijack this developmental circuitry to sustain their growth and establish an early immunosuppressive microenvironment during malignant progression. Recent work implicates CXCR4 + tissue‐resident macrophages (TRMs) in the mammary gland as a central orchestrator of this process. Conserved CXCL12/CXCR4‐AKT‐β‐catenin signaling links CXCR4 + 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‐associated fibroblasts promotes the expansion of CXCR4 + TRMs, while CXCR4 signaling enhances ALDH1A2‐dependent retinoic acid production, which induces regulatory T cells and thereby suppresses anti‐tumor 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–niche crosstalk constitutes a tractable vulnerability, and that incorporating TRM‐directed interventions alongside conventional and immune‐based therapies may shift the balance toward durable tumor control.