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

Zhao et al. Cell Communication and Signaling https://doi.org/10.1186/s12964-024-01743-2 (2024) 22:379 Cell Communication and Signaling Open Access REVIEW Cuproptosis, the novel type of oxidationinduced cell death in thoracic cancers: can it enhance the success of immunotherapy? Ruiwen Zhao1†, Olga Sukocheva2*†, Edmund Tse2, Margarita Neganova3, Yulia Aleksandrova3, Yufei Zheng1, Hao Gu1, Deyao Zhao1, SabbaRao V. Madhunapantula4, Xiaorong Zhu1, Junqi Liu1 and Ruitai Fan1* 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), drolipoamide 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 Ruitai Fan 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/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (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 with the regulation of mitochondrial respiration and oxidative stress in various cells, including malignant. • Changed concentration of copper ions was found to regulate a set of redox-metabolism-regulating genes, such as ferredoxin 1, lipoic acid synthetase, lipoyltransferase 1, dihydrolipoamide dehydrogenase, drolipoamide S-acetyltransferase, and pyruvate dehydrogenase E1 subunits alpha 1 and beta. • Cuproptosis-related genes and copper-containing compounds were indicated as potential targets and tools for the development of novel anti-cancer therapy. Open Questions • How to target cuproptosis-related genes to stop cancer cell survival? • Which copper-responsive targets and/or copper-containing compounds can be employed safely and effectively during cancer treatment? • Which biomarkers can be reliably employed to define good response to the activation of cuproptosis in cancer cells? • Are there others, undiscovered intracellular targets of copper which can be used for cancer prevention and treatment? Keywords Cancer therapy, Cuproptosis, Ferredoxin 1 (Fdx1), Tumor microenvironment (TME), Oxidative stress, Immunoediting Graphical Abstract Introduction Metal element copper is required for the effective functioning of human organisms. Copper is used as a micronutrient involved in several important catalytic processes as a structural cofactor of metal-dependent enzymes [1, 2]. The presence of this element is required for the metabolic regulation of growth and functional activities of the human body [3, 4]. The normal copper concentration, which is equal to about 1 mg/L in blood plasma and 50–120 mg for the total body content in average adults, is beneficial for the maintenance of proper homeostasis, while high or low concentrations of copper may be damaging for the optimal physiological state [5, 6]. Copper deficiency has been linked to diseases including anemia [7], osteoporosis [8], obesity [9], coronary heart diseases [10, 11], and cancers [6, 12]. Disorders of copper metabolism can also cause neurological pathologies, including Wilson’s [13], Alzheimer’s [14, 15], and Parkinson’s diseases [16–18]. A high concentration of copper is a cytotoxic, cell death-activating factor [19, 20]. Copper-induced cell death was defined as cuproptosis (terminology suggested by Tsvetkov [21]), a novel form of programmed cell death (PCD) that is different from apoptosis, necroptosis, pyroptosis, and ferroptosis [21, 22]. For instance, apoptosis is a classical PCD type which is marked by activation of several death pathways, chromatin condensation, caspase (-1, -3 and − 8) cleavage, and release of cytochrome c (cyt c) from mitochondria. Various internal physiological factors, such as cytokines and glucocorticoid hormones, can trigger PCD gene activation in apoptosis [23, 24]. The mitochondrion is the central intracellular organelle which is responsible for the propagation of classical apoptosis. Mitochondria are also affected during ferroptosis and cuproptosis. Unlike apoptosis, chromatin condensation and/or caspase − 3 cleavage were not reported during activation of ferroptosis or cuproptosis [25, 26]. Ferroptosis is a PCD trigged by the accumulation of iron ions, dysregulated iron metabolism, modified activation of specific iron-activated (...truncated)