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

Bone marrow is both a primary site for blood cell production and a fertile niche for cancer metastasis. The mechanism of common occurrence of anemia among patients with bone metastasis remains poorly understood. Here, we identified a specialized population of VCAM1+CD163+CCR3+ macrophages, which are typically essential for erythropoiesis, become highly enriched in bone metastatic niche and support tumor growth. Hijacking of these macrophages 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. Macrophages with similar iron-regulating features were found in human bone metastases, and elevated HBB expression correlates with increased risk of bone metastasis. These findings establish iron-recycling macrophages as an essential component of metastatic bone niche, revealing novel interplay between immune modulation, metal metabolism and tumor cell plasticity in driving metastatic progression and anemia.