Researchers have uncovered a critical explanation for why bone metastases in cancer patients often lead to anemia. The study, conducted by Y. Han et al using advanced cellular mapping and sequencing techniques, revealed that tumor cells manipulate specialized macrophages in bone marrow to divert iron away from red blood cell production, fueling their own survival. Further details appear in a paper published on 3 September 2025 in Cell.
Bone Metastasis Study Reveals How and Why Cancer Exploits Iron and Weakens Blood Formation
Overview of the Methodology and Findings
The seed and soil hypothesis, first proposed by English surgeon Stephen Paget in 1889, suggests that cancer spread or specific cancer metastasis depends not only on the malignant cells themselves but also on the environments of distant organs they encounter. Tumors are likened to seeds that flourish only in favorable microenvironments described as soil.
Bone metastases are common in advanced cancers, especially breast cancer and prostate cancer, and they are associated with high mortality. Around 70 percent of patients who die from these cancers develop bone metastases. Anemia has long been observed in these cases, but the biological mechanism remained poorly understood until now.
The researchers used in vivo niche labeling combined with single-cell RNA sequencing to trace and analyze macrophages within bone marrow. These cells normally function as iron suppliers to erythroblast islands, where red blood cells mature. Findings showed that tumors take over these macrophages. This redirects iron resources toward malignant growth.
Consequences of this interference are profound. Red blood cell development stalls during the enucleation stage. Note that this stage involves immature cells expelling their nuclei before reaching full maturity. This disruption lowers healthy red blood cell counts, directly explaining the frequent emergence of anemia in bone metastasis patients.
The researchers also discovered that tumor cells adapt to low-oxygen bone environments by mimicking erythroblasts. They activate the transcription factor GATA1. This protein normally governs red blood cell maturation. This adaptation allows cancer cells to produce hemoglobin and gives them the ability to capture iron and survive under hypoxic conditions.
Specific Details of the Primary Findings
The findings are significant because they highlight the role of the bone marrow microenvironment in disease progression. The seed and soil hypothesis has emphasized the interaction between tumor cells and supportive environments for over a century. This study provides concrete evidence that manipulation of the soil directly drives cancer complications.
• Hijacking of Macrophages: Tumor cells divert erythroblast island macrophages from their role in supplying iron to red blood cells, forcing them to provide iron to malignant cells instead. This resource diversion contributes directly to the development of anemia in patients with bone metastasis.
• Disrupted Red Blood Cell Maturation: Moreover, when macrophages are diverted, red blood cells fail to complete enucleation, leaving immature cells unable to mature. This process sharply reduces healthy red blood cell counts, explaining why anemia is so prevalent in bone metastasis cases.
• Erythroblast Mimicry by Tumors: Cancer cells activate GATA1, a transcription factor critical for red blood cell gene expression. By doing so, tumors mimic erythroblasts and produce hemoglobin. This adaptation enables them to use iron efficiently and thrive in bone marrow environments.
• Enhanced Hypoxic Survival: The ability to produce hemoglobin allows tumor cells to endure oxygen-poor conditions within the bone. This metabolic shift gives tumors a survival advantage in areas that would otherwise be inhospitable, ensuring their persistence despite environmental challenges.
Implications for Oncology and Future Research
Although the research focused primarily on breast cancer, the biological mechanisms described are expected to extend to prostate and other malignancies that commonly spread to bone. With a large majority of patients succumbing to these cancers showing bone involvement, the discovery is likely to reshape future therapeutic strategies.
The therapeutic potential of the aforementioned findings is considerable. Strategies that prevent macrophage commandeering, restore proper iron delivery, or block tumor mimicry could reduce anemia while also impairing tumor growth. Such dual benefits could improve both patient outcomes and quality of life in advanced cancer stages.
Specifically, by revealing the mechanism of anemia in bone metastasis, this research provides answers to a long-standing medical question. It shows how tumors exploit the iron recycling system of the bone marrow and identifies new vulnerabilities that can be targeted for treatment. The work advances both clinical practice and theoretical oncology.
FURTHER READING AND REFERENCE
- Han, Y., Sarkar, H., Xu, Z., Lopez-Darwin, S., Wei, Y., Hang, X., Liu, F., Tran, K., Wang, W., Miller, J. M., DeCoste, C. J., Blohm, D. S., Satcher, R. L., Zhang, X. H.-F., and Kang, Y. 2025. “Tumors Hijack Macrophages for Iron Supply to Promote Bone Metastasis and Anemia.” Cell. DOI: 1016/j.cell.2025.08.013