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Broadening horizons: the role of ferroptosis in cancer

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Abstract

The discovery of regulated cell death processes has enabled advances in cancer treatment. In the past decade, ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has been implicated in the development and therapeutic responses of various types of tumours. Experimental reagents (such as erastin and RSL3), approved drugs (for example, sorafenib, sulfasalazine, statins and artemisinin), ionizing radiation and cytokines (such as IFNγ and TGFβ1) can induce ferroptosis and suppress tumour growth. However, ferroptotic damage can trigger inflammation-associated immunosuppression in the tumour microenvironment, thus favouring tumour growth. The extent to which ferroptosis affects tumour biology is unclear, although several studies have found important correlations between mutations in cancer-relevant genes (for example, RAS and TP53), in genes encoding proteins involved in stress response pathways (such as NFE2L2 signalling, autophagy and hypoxia) and the epithelial-to-mesenchymal transition, and responses to treatments that activate ferroptosis. Herein, we present the key molecular mechanisms of ferroptosis, describe the crosstalk between ferroptosis and tumour-associated signalling pathways, and discuss the potential applications of ferroptosis in the context of systemic therapy, radiotherapy and immunotherapy.

Key points

  • Ferroptosis is a form of regulated cell death that mainly relies on iron-mediated oxidative damage and subsequent cell membrane damage.

  • Ferroptosis can be initiated through two major pathways: the extrinsic or transporter-dependent pathway, and the intrinsic or enzyme-regulated pathway.

  • The increase in iron accumulation, free radical production, fatty acid supply and lipid peroxidation by dedicated enzymes is critical for the induction of ferroptosis.

  • Multiple oxidative and antioxidant systems, acting together with the autophagy and membrane repair machinery, shape the process of lipid peroxidation during ferroptosis.

  • In tumorigenesis, ferroptosis has a dual role in tumour promotion and suppression, which depends on the release of damage-associated molecular patterns and the activation of immune response triggered by ferroptotic damage within the tumour microenvironment.

  • Ferroptosis affects the efficacy of chemotherapy, radiotherapy and immunotherapy, and thus combinations with agents targeting ferroptosis signalling could improve the outcomes from those therapies.

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Fig. 1: Molecular mechanisms of ferroptosis.
Fig. 2: Iron metabolism in ferroptosis.
Fig. 3: Role of EMT in ferroptosis.
Fig. 4: Role of ferroptosis in tumour immunity.
Fig. 5: Role of ferroptosis in radiotherapy.

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Acknowledgements

We thank D. Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the manuscript. G.K. is supported by the Agence National de la Recherche (ANR)–Projets blancs; ANR under the frame of the ERA-Net for Research on Rare Diseases (E-Rare-2); Association pour la recherche sur le cancer; Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix); a donation from Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Fondation Carrefour; Fondation pour la Recherche Médicale; Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; High-end Foreign Expert Program in China (GDW20171100085 and GDW20181100051); Inserm (HTE); Institut National du Cancer; Institut Universitaire de France; LabEx Immuno-Oncology; LeDucq Foundation; Ligue contre le Cancer (équipe labellisée); RHU Torino Lumière; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM).

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Chen, X., Kang, R., Kroemer, G. et al. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol 18, 280–296 (2021). https://doi.org/10.1038/s41571-020-00462-0

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