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Updated: Jan 9, 2026
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Macrophages rescue cells from ferroptotic death
Ruth Hefetz1, Sapir Harush2, Lucy Ghantous1
1Goldyne Savad Institute of Gene Therapy, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Abstract:
Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation, has a key role in organ injury, degenerative disease, and vulnerability of therapy-resistant cancers. Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we demonstrate that macrophages co-cultured with ferroptotic cancer cells from various types effectively mitigate cell death induced by GPX4 inhibitors (RSL3 and ML162), GPX4 silencing via shRNA, or the Xc- system inhibitor IKE. Furthermore, macrophages effectively reduced lipid peroxidation in ferroptotic cells. Importantly, macrophage function relies on direct cell-to-cell contact and is affected by their differentiation. Specifically, polarization into M1 macrophages, but not M2, greatly hinders their protective capabilities. Interestingly, unlike apoptotic cells, ferroptotic cells retain elevated levels of the 'don't eat me' signal, CD47, and conversely, fail to present the "eat me" signal phosphatidylserine (PS) on the outer layer of the plasma membrane, providing an opportunity for their rescue. Furthermore, in placental villi explants, macrophages protect trophoblasts from ferroptotic death. These results underscore the intricate interplay between ferroptotic cells and their microenvironment and provide compelling evidence of a yet-unrecognized anti-ferroptotic activity of macrophages as a cell-extrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.
Insights
Macrophages can prevent cancer cells from dying via ferroptosis, a process involving iron and lipid peroxidation. This protective effect, mediated by cell-to-cell contact, is reduced when macrophages polarize into M1 types.
Area of Science:
- Cell biology
- Immunology
- Cancer research
Background:
- Ferroptosis, an iron-dependent form of cell death, plays a role in organ injury, degenerative diseases, and cancer therapy resistance.
- While intracellular mechanisms of ferroptosis are known, extracellular factors influencing cell sensitivity remain unclear.
Purpose of the Study:
- To investigate the role of macrophages in modulating ferroptosis in cancer cells.
- To identify the mechanisms by which macrophages influence ferroptosis and explore potential therapeutic applications.
Main Methods:
- Co-culture of various cancer cell types with macrophages.
- Induction of ferroptosis using GPX4 inhibitors (RSL3, ML162), GPX4 silencing, or Xc- system inhibitor (IKE).
- Assessment of cell death, lipid peroxidation, and cell surface markers (CD47, phosphatidylserine) in ferroptotic cells.
- Evaluation of macrophage differentiation (M1 vs. M2) and cell-to-cell contact dependency.
Main Results:
- Macrophages significantly reduced ferroptosis and lipid peroxidation in cancer cells, irrespective of the ferroptosis inducer.
- Macrophage protection was dependent on direct cell-to-cell contact.
- M1-polarized macrophages exhibited reduced protective capabilities compared to M2.
- Ferroptotic cells displayed elevated CD47 ('don't eat me' signal) and reduced phosphatidylserine (PS, 'eat me' signal), facilitating macrophage interaction.
- Macrophages protected trophoblasts from ferroptosis in placental villi explants.
Conclusions:
- Macrophages possess an unrecognized anti-ferroptotic activity, acting as a cell-extrinsic protective mechanism.
- Cancer cells may exploit this macrophage-mediated protection to escape ferroptosis.
- Understanding this interaction is crucial for developing novel cancer therapies targeting ferroptosis.
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