Macrophages and macrophage extracellular vesicles confer cancer ferroptosis resistance via PRDX6-mediated mitophagy inhibition
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Updated: Sep 11, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Naisheng Zheng1, Fuli Li1, Qing Huang1
1Institute of Molecular Medicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, PR China.
Abstract:
Ferroptosis has emerged as a promising therapeutic target in cancer therapy, with the tumor microenvironment (TME) playing a pivotal role in regulating ferroptosis. Although macrophages contribute to ferroptosis regulation within TME, the underlying mechanisms remain unclear. In this study, we demonstrate that macrophages consistently attenuate GPX4 inhibitor-induced lipid peroxidation and cell death in various tumor cell lines, whereas their resistance to cysteine transport inhibitor-triggered ferroptosis varies across cell types. This tumor protection from ferroptosis is mediated through macrophage-tumor cell contact and the delivery of macrophage-derived extracellular vesicles (Mφ-EV). Transcriptomic and proteomic analyses revealed that macrophages and Mφ-EV enhance glutathione metabolism in tumor cells. Notably, Mφ-EV are uniquely enriched with the glutathione metabolism-related protein PRDX6. Mechanistically, the glutathione peroxidase activity of PRDX6 elevates intracellular reduced glutathione, suppresses lipid peroxidation, and thereby mitigates ferroptosis. Furthermore, macrophage-derived PRDX6 reduces mitochondrial superoxide accumulation, alleviates ferroptosis-induced mitophagy, and enhances tumor cell viability, ultimately promoting tumor growth. Together, our findings provide a novel mechanism of ferroptosis resistance in TME, wherein macrophages confer tumor cell resilience by bypassing GPX4 inhibition.
Insights
Macrophages protect tumor cells from ferroptosis, a cancer therapy target, by enhancing glutathione metabolism via extracellular vesicles. This mechanism bypasses GPX4 inhibition, promoting tumor growth and offering new therapeutic insights.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Ferroptosis is a key target in cancer therapy.
- The tumor microenvironment (TME) influences ferroptosis.
- Macrophages' role in TME ferroptosis regulation is not fully understood.
Purpose of the Study:
- Investigate how macrophages regulate ferroptosis in the TME.
- Elucidate the mechanisms by which macrophages confer ferroptosis resistance to tumor cells.
- Identify specific molecular mediators involved in macrophage-mediated ferroptosis suppression.
Main Methods:
- Utilized various tumor cell lines and macrophage co-culture models.
- Employed GPX4 and cysteine transport inhibitors to induce ferroptosis.
- Conducted transcriptomic and proteomic analyses.
- Investigated the role of macrophage-derived extracellular vesicles (Mφ-EV) and PRDX6.
Main Results:
- Macrophages attenuated GPX4 inhibitor-induced ferroptosis but showed variable resistance to cysteine transport inhibitors.
- Macrophage-tumor cell contact and Mφ-EV mediated ferroptosis protection.
- Macrophages and Mφ-EV enhanced tumor cell glutathione metabolism.
- Mφ-EV were enriched with PRDX6, which mitigated ferroptosis by boosting reduced glutathione and suppressing lipid peroxidation.
- Macrophage-derived PRDX6 reduced mitochondrial superoxide, alleviated mitophagy, and promoted tumor cell viability.
Conclusions:
- Macrophages confer ferroptosis resistance to tumor cells through PRDX6 delivered via Mφ-EV.
- This mechanism enhances tumor cell resilience by bypassing GPX4 inhibition.
- Findings reveal a novel pathway of ferroptosis evasion in the TME, offering potential therapeutic targets.
