Iron Metabolism in Macrophage Function and Cancer Biology

Iron is essential for numerous cellular processes, including oxygen transport, DNA synthesis and energy metabolism. Macrophages are central regulators of systemic and local iron homeostasis: they recycle iron from senescent erythrocytes via erythrophagocytosis, store excess iron in ferritin and export iron through the ferroportin channel under the control of the hepatic peptide hepcidin. In the tumour microenvironment, macrophages adopt context-dependent phenotypes that are influenced by iron availability. Iron-rich macrophages can drive pro-inflammatory or anti-tumoral responses through reactive oxygen species generation and modulation of ferroptosis sensitivity in surrounding cell populations. Conversely, tumour-associated macrophages often exhibit an iron-donating phenotype, releasing iron to support malignant cell proliferation and suppress immune surveillance. Dysregulation of these processes contributes to tumour progression, chemoresistance and cancer-related anaemia. Targeting macrophage iron handling—through iron chelation, modulation of the hepcidin–ferroportin axis or delivery of ferroptosis inducers—holds promise for novel therapeutic strategies in cancer and inflammatory diseases.

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Iron Metabolism in Macrophage Function and Cancer Biology publication trend

The graph below shows the total number of articles in iron metabolism in macrophage function and cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Ferroptosis: A form of regulated cell death driven by iron-dependent lipid peroxidation.

Tumour-associated macrophages (TAMs): Macrophages within the tumour microenvironment that can support or inhibit tumour growth depending on their activation state.

Hepcidin: A liver-derived peptide hormone that regulates systemic iron levels by inducing internalisation of ferroportin.

Ferroportin: The only known iron exporter on cell membranes, responsible for releasing iron into the circulation.

Transferrin receptor 1 (TfR1): A cell-surface protein that mediates uptake of transferrin-bound iron into cells.

Reactive oxygen species (ROS): Chemically reactive molecules containing oxygen, which can damage cellular components and drive signalling pathways.

References

1. Coculture with macrophages alters ferroptosis susceptibility of triple-negative cancer cells. Cell Death Discovery (2024).
2. Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment. Oxidative Medicine and Cellular Longevity (2021).
3. Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl‐p53 pathway. Cancer Medicine (2018).
4. Ironing Out the Details: How Iron Orchestrates Macrophage Polarization. Frontiers in Immunology (2021).
5. Regulation of tissue iron homeostasis: the macrophage “ferrostat”. JCI Insight (2020).
6. Iron Metabolism in the Tumor Microenvironment: Contributions of Innate Immune Cells. Frontiers in Immunology (2021).
7. On Iron Metabolism and Its Regulation. International Journal of Molecular Sciences (2021).