Niche Macrophages Recycle Iron to Tumor Cells and Foster Erythroblast Mimicry to Promote Bone Metastasis and Anemia

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Abstract Bone marrow is both a primary site for blood cell production and a fertile niche for metastatic cancer cell growth, notably in breast cancer. Although anemia is common among patients with bone metastasis, the mechanistic link between metastatic colonization and disrupted erythropoiesis remains poorly understood. Using in vivo niche labeling and single-cell RNA sequencing, we identified a specialized population of VCAM1 + CD163 + CCR3 + macrophages enriched in the bone metastatic niche. These macrophages, typically essential for erythropoiesis in healthy bone marrow, are co- opted by tumor cells to support their growth through iron acquisition. The hijacking of these macrophages by tumor cells reduces iron availability for erythroblasts, impairing erythropoiesis and contributing to anemia. With increased iron supply, tumor cells further adapt by mimicking erythroblasts, producing hemoglobin under GATA1 regulation in response to hypoxic stress. Notably, macrophages with similar iron- regulating features were found in human bone metastases across multiple cancer types, and elevated HBB expression in breast cancer correlates with increased risk of bone metastasis. These findings establish iron-recycling macrophages as essential regulators within the metastatic bone niche, revealing novel insights into the interplay between immune modulation, metal metabolism and tumor cell plasticity in driving metastatic progression and anemia.

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