OPINION

Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion

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Abstract

Ferroptosis is a recently recognized cell death modality that is morphologically, biochemically and genetically distinct from other forms of cell death and that has emerged to play an important role in cancer biology. Recent discoveries have highlighted the metabolic plasticity of cancer cells and have provided intriguing insights into how metabolic rewiring is a critical event for the persistence, dedifferentiation and expansion of cancer cells. In some cases, this metabolic reprogramming has been linked to an acquired sensitivity to ferroptosis, thus opening up new opportunities to treat therapy-insensitive tumours. However, it is not yet clear what metabolic determinants are critical for therapeutic resistance and evasion of immune surveillance. Therefore, a better understanding of the processes that regulate ferroptosis sensitivity should ultimately aid in the discovery of novel therapeutic strategies to improve cancer treatment. In this Perspectives article, we provide an overview of the known mechanisms that regulate sensitivity to ferroptosis in cancer cells and how the modulation of metabolic pathways controlling ferroptosis might reshape the tumour niche, leading to an immunosuppressive microenvironment that promotes tumour growth and progression.

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Fig. 1: The main metabolic processes regulating ferroptosis and GPX4 activity.
Fig. 2: Hypothetical model of an inverse correlation of the cellular peroxide tone and immune evasion.
Fig. 3: Possible modulation of tumour immunity by ferroptotic cancer cells.

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Acknowledgements

J.P.F.A. is supported by the Junior Group Leader programme of the Rudolf Virchow Center, University of Würzburg. D.V.K. is supported by FWO-Flanders (1506218 N, 1507118 N, G051918N and 3G043219) and Ghent University (Special Research Fund; BOF14-GOA-019 and IOP 01/O3618). M.C. is supported by the Deutsche Forschungsgemeinschaft (DFG) CO 291/5-2, the German Federal Ministry of Education and Research (BMBF) through the Joint Project Modelling ALS Disease In Vitro (MAIV; 01EK1611B) and the VIP+ programme NEUROPROTEKT (03VP04260), as well as the m4 Award provided by the Bavarian Ministry of Economic Affairs, Regional Development and Energy (StMWi). The authors would also like to apologize to all colleagues whose work could not be cited owing to space limitations.

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Nature Reviews Cancer thanks X. Jiang, P. Meier and other anonymous reviewer(s) for their contribution to the peer review of this work.

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The authors contributed equally to all aspects of the article.

Correspondence to José Pedro Friedmann Angeli or Marcus Conrad.

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Glossary

β-Oxidation

A catabolic process in which fatty acid molecules are oxidized in mitochondria to generate acetyl-CoA, NADH and FADH, the last two of which drive forces of the electron transport chain.

Conventional type 1 dendritic cell

(cDC1). A subset of dendritic cells dependent on the transcription factor BATF3 for development and characterized by the specific expression of C-type lectin receptor DNGR1.

Eicosanoids

Bioactive metabolites derived from the enzymatic and non-enzymatic oxidation of arachidonic acid and other polyunsaturated fatty acids that are 20 carbon units in length.

Labile iron pool

A transient pool of chelatable redox-active iron.

Mevalonate pathway

A metabolic pathway responsible for the generation of sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids including dolichol, haem A, isopentenyl tRNA and ubiquinone.

Necrotic cell death

In contrast to the prototype of programmed cell death, that is, apoptosis, this umbrella term is used to identify cells that share similar terminal features that include, but are not limited to, extracellular extravasation and immunogenicity.

Peroxidatic cysteine

A cysteine residue found in the catalytic site of several redoxins that is responsible for the nucleophilic attack of a peroxide bond.

Transsulfuration pathway

A metabolic pathway responsible for the interconversion of methionine to cysteine.

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