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  3. Tumors hijack macrophages for iron supply to promote bone metastasis and anemia

Tumors hijack macrophages for iron supply to promote bone metastasis and anemia

  • Cell. 2025 Aug 26:S0092-8674(25)00927-4. doi: 10.1016/j.cell.2025.08.013.
Yujiao Han 1,  Hirak Sarkar 2,  Zhan Xu 3,  Sereno Lopez-Darwin 4,  Yong Wei 1,  Xiang Hang 1,  Fengshuo Liu 5,  Kimberley Tran 6,  Wei Wang 4,  Jennifer M Miller 4,  Christina J DeCoste 6,  Dylan S Blohm 6,  Robert L Satcher 7,  Xiang H-F Zhang 8,  Yibin Kang 9
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA; Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ 08544, USA.
  • 2 Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ 08544, USA; Department of Computer Science, Princeton University, Princeton, NJ 08544, USA.
  • 3 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 4 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
  • 5 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Cancer and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 6 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 7 Department of Orthopedic Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 8 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 9 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA; Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ 08544, USA; Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA. Electronic address: ykang@princeton.edu.
PMID: 40907490 DOI: 10.1016/j.cell.2025.08.013
Abstract

Bone marrow is both a primary site for hematopoiesis and a fertile niche for metastasis. The mechanism of the common occurrence of anemia among patients with bone metastasis remains poorly understood. Here, we show that a specialized population of VCAM1+CD163+CCR3+ macrophages, normally essential for erythropoiesis by transporting iron to erythroblasts, are highly enriched in the bone metastatic niche in mouse models. Tumor cells hijack these macrophages for iron supply, reducing iron availability for erythroblasts, impairing erythropoiesis, and contributing to anemia. Increased iron supply enables tumor cells to produce Hemoglobin in response to hypoxia, mimicking erythroblasts. We identify macrophages with similar iron-transporting features in human bone metastases and show that elevated HBB expression correlates with increased risk of bone metastasis. These findings establish iron-transporting macrophages as an essential component of the metastatic bone niche, revealing a critical interplay between immune cells, metal metabolism, and tumor cell plasticity in driving metastasis and anemia.

Keywords

anemia; bone metastasis; breast cancer; cellular plasticity; erythropoiesis; hypoxia; iron metabolism; macrophage; metastatic niche; tumor microenvironment.

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