Cuproptosis, the novel type of oxidation-induced cell death in thoracic cancers: can it enhance the success of immunotherapy?

Sep 21, 2026

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Copper is a key micronutrient needed for normal growth and physiological function, while copper imbalance and toxicity disrupt intracellular respiration and contribute to disease, including cancer. Copper-induced cell death, called cuproptosis, is observed in malignant cells and is linked to aggregation of lipoylation proteins and activation of cell-death pathways under toxic copper excess. Cuproptosis-related gene expression differs between normal and tumor tissues and associates with oxidative stress control, immune responses, and tumor microenvironment composition. Activation of cuproptosis correlates with redox-metabolism regulators such as FDX1, LIAS, LIPT1, DLD, DLAT, PDHA1, and PDHB, suggesting copper signaling as a therapeutic target to improve immunotherapy outcomes.

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CategoryHealthcare

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Zhao et al. Cell Communication and Signaling (2024) 22:379 [https://doi.org/10.1186/s12964-024-01743-2](https://doi.org/10.1186/s12964-024-01743-2) Cell Communication and Signaling REVIEW Open Access Cuproptosis, the novel type of oxidationinduced cell death in thoracic cancers: can it enhance the success of immunotherapy? Ruiwen Zhao 1†, Olga Sukocheva2*†, Edmund Tse2, Margarita Neganova3, Yulia Aleksandrova3, Yufei Zheng 1, Hao Gu 1, Deyao Zhao 1, SabbaRaoV. Madhunapantula4, Xiaorong Zhu 1, Junqi Liu 1 and Ruitai Fan 1* Abstract Copper is an important metal micronutrient, required for the balanced growth and normal physiological functions of human organism. Copper-related toxicity and dysbalanced metabolism were associated with the disruption of intracellular respiration and the development of various diseases, including cancer. Notably, copper-induced cell death was defined as cuproptosis which was also observed in malignant cells, representing an attractive anticancer instrument. Excess of intracellular copper leads to the aggregation of lipoylation proteins and toxic stress, ultimately resulting in the activation of cell death. Differential expression of cuproptosis-related genes was detected in normal and malignant tissues. Cuproptosis-related genes were also linked to the regulation of oxidative stress, immune cell responses, and composition of tumor microenvironment. Activation of cuproptosis was associated with increased expression of redox-metabolism-regulating genes, such as ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS), lipoyltransferase 1 (LIPT1), dihydrolipoamide dehydrogenase (DLD), drol ipoamide S-acetyltransferase (DLAT), pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), and pyruvate dehydrogenase E1 subunit beta (PDHB)) . Accordingly, copper-activated network was suggested as an attractive target in cancer therapy. Mechanisms of cuproptosis and regulation of cuproptosis-related genes in different cancers and tumor microenvironment are discussed in this study. The analysis of current findings indicates that therapeutic regulation of copper signaling, and activation of cuproptosis-related targets may provide an effective tool for the improvement of immunotherapy regimens. Key messages Facts • Copper ions, essential components of human body, can activate a novel subtype of programmed cell death, defined as cuproptosis. †Ruiwen Zhao and Olga Sukocheva contributed equally to this work. *Correspondence: Olga Sukocheva [olga.sukocheva@sa.gov.au](olga.sukocheva@sa.gov.au)[ ](olga.sukocheva@sa.gov.au)Ruitai Fan [fccfanrt@zzu.edu.cn](fccfanrt@zzu.edu.cn) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/l](http://creativecommons.org/l)icenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ([http://creativecommons.org/publicdomain/zero/1.0/](http://creativecommons.org/publicdomain/zero/1.0/)) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhao et al. Cell Communication and Signaling (2024) 22:379 Page 2 of 18 • Cuproptosis is tightly associated wit

FAQs

What is cuproptosis and how does it relate to copper in thoracic cancers?

Cuproptosis is copper-induced cell death defined as a novel programmed cell death subtype observed in malignant cells. Excess intracellular copper triggers aggregation of lipoylation proteins and toxic stress, activating cell death pathways.

Which genes are associated with cuproptosis activation?

Cuproptosis activation is linked to increased expression of redox-metabolism-regulating genes such as FDX1, LIAS, LIPT1, DLD, DLAT, PDHA1, and PDHB. Cuproptosis-related genes also relate to oxidative stress and immune-related processes.

How might targeting cuproptosis improve immunotherapy?

The study indicates that therapeutic regulation of copper signaling and activation of cuproptosis-related targets may provide an effective approach to enhance immunotherapy regimens. It frames copper-responsive targets and biomarkers as important for safe, effective cancer treatment.

Sep 21, 2026

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