Tumor cells steal iron from macrophages to thrive during bone metastasis

Bone marrow is both a primary site of blood cell production and a frequent site of cancer spread, particularly in breast cancer.Anemia, a conditioned characterized by red blood cell (RBC) deficiency, is common in patients with bone metastases, in which cancer cells spread from the original tumors to the bones, but the underlying mechanisms of how they are connected are not well defined.Using an in vivo proximity-labelling system in a living organism, combined with single-cell RNA sequencing, a method that takes a 'snapshot' of what each individual cell is doing by measuring its gene activity based RNA express levels, we identified a rare population of macrophages (immune cells that act as "clean-up crew") with iron recycling features that are enriched in the breast cancer bone metastatic niche.Under normal conditions, these macrophages support erythropoiesis, the process of making RBCs, by recycling iron for RBC production.In the metastatic setting, however, tumor cells hijack these macrophages to obtain iron, impairing their ability to sustain RBC formation and contributing to anemia.In response to limited oxygen and iron availability, metastatic tumor cells display striking plasticity, an ability to change its cellular identity and behavior in response to its environment, by acting like erythroblasts, the RBC precursors.This "erythroblast mimicry" helps tumor cells adapt to the hypoxic (low-oxygen) bone marrow microenvironment.Importantly, iron-handling macrophages with similar transcriptional features to those identified in our mouse models were also found in human bone metastases, and elevated hemoglobin (Hgb) expression in tumor cells was associated with increased risk of bone metastasis.Our findings reveal a previously unrecognized role of iron-recycling macrophages in the bone metastatic niche and uncover a previously unrecognized tumor-immune-metabolic axis that accelerates bone metastasis progression and contributes to cancer-associated anemia.