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Extracellular GPX4 functions as an immunosuppressive DAMP in ferroptosis

Cell Death & Differentiation (2026) Cite this article

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In a recent study published in Cell, Liu et al. identified glutathione peroxidase 4 (GPX4) as a novel immunosuppressive damage-associated molecular pattern (DAMP) that is specifically released by cancer cells undergoing ferroptosis. By binding to dendritic cell (DC) zona pellucida glycoprotein 3 (ZP3) receptors, extracellular GPX4 impairs DC maturation and activation, thereby indirectly suppressing CD8⁺ T cell priming and the immunogenicity of ferroptotic cancer cells [1]. This work not only reveals a previously unrecognized immunosuppressive axis intrinsic to ferroptosis but also highlights the GPX4–ZP3 interaction as a promising target for combined antitumor therapies.

The efficacy of modern anticancer regimens depends on their ability to induce immunogenic cell death (ICD), a process in which dying tumor cells emit or release DAMPs that activate DCs and prime adaptive T-cell immunity. It is now recognized that the functional definition of DAMPs has expanded beyond prototypically immunostimulatory signals to include immunosuppressive mediators, reflecting the complexity of immune regulation during cell death. Ferroptosis is an iron-dependent form of regulated cell death (RCD) driven by overwhelming membrane phospholipid peroxidation upon collapse of antioxidant defenses, notably the system xc−–glutathione peroxidase 4 (GPX4) axis or the ferroptosis suppressor protein 1 (FSP1) pathway. Over the past decade, ferroptosis has attracted considerable attention for its potency against apoptosis-resistant tumors and its contribution to the effects of immunotherapy, radiotherapy, and certain chemotherapeutic agents. Notably, cytotoxic CD8+ T cells can promote tumor ferroptosis via interferon-γ, suggesting a role for ferroptosis in natural anticancer immunosurveillance [2]. However, whether cancer cell ferroptosis constitutes a bona fide ICD modality remains controversial. On one hand, early ferroptotic fibrosarcoma cells have been shown to release DAMPs such as ATP and HMGB1, thereby promoting DC maturation and activating adaptive immune responses [3]. Tumor-specific GPX4 degradation by N6F11 induces immunogenic ferroptosis and exhibits prophylactic activity in gold-standard vaccination assays [4]. On the other hand, recent studies indicate that ferroptotic cancer cells inhibit DC maturation and fail to elicit robust immunogenicity compared to cells undergoing apoptosis or necroptosis, despite DAMP release [5], suggesting that additional determinants likely exist and shape the immunogenicity of ferroptotic cancer cells.

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Fig. 1: The immunosuppressive GPX4–ZP3 axis in ferroptotic immunogenicity and its therapeutic intervention.
The alternative text for this image may have been generated using AI.

References

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Acknowledgements

We would like to thank BioRender (https://www.biorender.com/) for the assistance with the illustration.

Funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 82272849 to GD, 82130090 to XC, 82221002 to XC), Huxiang Youth Talent Program (Grant No. 2023RC3072 to GD), and Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China (Grant No. JYB2025XDXM603).

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  1. These authors contributed equally: Yu Meng, Daishi Li.

Authors and Affiliations

  1. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China

    Yu Meng, Daishi Li, Xiang Chen & Guangtong Deng

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  1. Yu Meng
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  2. Daishi Li
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  3. Xiang Chen
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Yu Meng wrote the draft and drew the figures. Daishi Li revised the manuscript. Guangtong Deng and Xiang Chen designed, revised, and finalized the manuscript. All authors have read and approved the manuscript.

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Correspondence to Xiang Chen or Guangtong Deng.

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Meng, Y., Li, D., Chen, X. et al. Extracellular GPX4 functions as an immunosuppressive DAMP in ferroptosis. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01728-3

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