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  • Review Article
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Targeting cuproplasia and cuproptosis in cancer

Nature Reviews Clinical Oncology volume 21, pages 370–388 (2024)Cite this article

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Abstract

Copper, an essential trace element that exists in oxidized and reduced forms, has pivotal roles in a variety of biological processes, including redox chemistry, enzymatic reactions, mitochondrial respiration, iron metabolism, autophagy and immune modulation; maintaining copper homeostasis is crucial as both its deficiency and its excess are deleterious. Dysregulated copper metabolism has a dual role in tumorigenesis and cancer therapy. Specifically, cuproplasia describes copper-dependent cell growth and proliferation, including hyperplasia, metaplasia and neoplasia, whereas cuproptosis refers to a mitochondrial pathway of cell death triggered by excessive copper exposure and subsequent proteotoxic stress (although complex interactions between cuproptosis and other cell death mechanisms, such as ferroptosis, are likely and remain enigmatic). In this Review, we summarize advances in our understanding of copper metabolism, the molecular machineries underlying cuproplasia and cuproptosis, and their potential targeting for cancer therapy. These new findings advance the rapidly expanding field of translational cancer research focused on metal compounds.

Key points

  • Copper is an essential trace element that has crucial roles in both normal physiological processes and pathological processes, including cancer.

  • Cuproplasia is a term used to describe the role of copper in promoting cell proliferation and growth.

  • Cuproptosis is a type of mitochondrial cell death driven by proteotoxic stress associated with protein lipoylation and degradation of Fe–S cluster proteins.

  • Ferredoxin 1 has a key role in cuproptosis by reducing Cu(II) to Cu(I) in mitochondria, facilitating excessive protein lipoylation and subsequent aggregation related to mitochondrial respiration.

  • Cuproplasia-related and/or cuproptosis-related genes have potential prognostic relevance in cancer owing to their influence on tumour growth, therapeutic responses and, ultimately, patient outcomes.

  • Both copper chelators and copper ionophores can suppress tumour growth and enhance chemotherapy, immunotherapy or radiation therapy by suppressing cuproplasia and inducing cuproptosis, respectively.

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Fig. 1: Summary of pathways mediating copper metabolism.
Fig. 2: Mechanisms of cuproplasia.
Fig. 3: Mechanisms of cuproptosis.
Fig. 4: Influence of copper on iron metabolism and ferroptosis.

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Acknowledgements

Research by D.T. and R.K. is supported by grants from the US National Institutes of Health (R01CA160417, R01CA229275, R01CA211070 and R01GM127791). The work of G.K. is supported by the Agence National de la Recherche (ANR)–Projets blancs; ANR under the framework 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 by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Fondation Carrefour; Fondation pour la Recherche Médicale; Gustave Roussy Odyssea; European Union Horizon 2020 Project Oncobiome; National High-end Foreign Expert Recruitment Plan of China (GDW20171100085 and GDW20181100051); 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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Authors and Affiliations

  1. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA

    Daolin Tang & Rui Kang

  2. Centre de Recherche des Cordeliers, INSERM U1138, Equipe labellisée–Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Institut Universitaire de France, Paris, France

    Guido Kroemer

  3. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France

    Guido Kroemer

  4. Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, Paris, France

    Guido Kroemer

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Tang, D., Kroemer, G. & Kang, R. Targeting cuproplasia and cuproptosis in cancer. Nat Rev Clin Oncol 21, 370–388 (2024). https://doi.org/10.1038/s41571-024-00876-0

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