Cuproptosis: unveiling a new frontier in cancer biology and therapeutics

Feng et al. Cell Communication and Signaling https://doi.org/10.1186/s12964-024-01625-7 Cell Communication and Signaling (2024) 22:249 Open Access REVIEW Cuproptosis: unveiling a new frontier in cancer biology and therapeutics Ying Feng1†, Zhibo Yang2†, Jianpeng Wang3 and Hai Zhao3* Abstract Copper plays vital roles in numerous cellular processes and its imbalance can lead to oxidative stress and dysfunction. Recent research has unveiled a unique form of copper-induced cell death, termed cuproptosis, which differs from known cell death mechanisms. This process involves the interaction of copper with lipoylated tricarboxylic acid cycle enzymes, causing protein aggregation and cell death. Recently, a growing number of studies have explored the link between cuproptosis and cancer development. This review comprehensively examines the systemic and cellular metabolism of copper, including tumor-related signaling pathways influenced by copper. It delves into the discovery and mechanisms of cuproptosis and its connection to various cancers. Additionally, the review suggests potential cancer treatments using copper ionophores that induce cuproptosis, in combination with small molecule drugs, for precision therapy in specific cancer types. Keywords Cuproptosis, Copper, Immunotherapy, Targetted therapy, Copper homeostasis, Mitochondria Introduction In recent years, the discovery of cuproptosis has not only challenged the conventional understanding of the role of copper in cellular death mechanisms but also opened new avenues in cancer research. From our perspective, cuproptosis represents a paradigm shift suggesting our approach to cancer therapeutics may be fundamentally transformed by targeting copper metabolism [1]. Copper, an essential trace element, plays a pivotal role in numerous cellular signaling pathways and is linked to cancer biology [2–5]. Historically, the pathways and forms of copper-induced cell death were not well-defined until a † Ying Feng and Zhibo Yang contributed equally to this work. *Correspondence: Hai Zhao 1 Department of Emergency, the Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266005, Shandong, China 2 Department of Neurosurgery, 3201 Hospital of Xi’an Jiaotong University Health Science Center, Hanzhong 723000, Shaanxi, China 3 Department of Neurosurgery, the Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao 266005, Shandong, China study suggested cuproptosis as a distinct mechanism, closely associated with mitochondrial respiration and the lipoic acid pathway, marking a significant advancement in understanding the role of copper in cell death [1]. A significant number of researchers are investigating the critical connection between cuproptosis and various types of cancer [6–8]. Strong association has been identified with cellular metabolism and the heightened levels of aerobic respiration seen in certain cancers like melanoma, breast cancer, and leukemia [9–12]. This relationship extends to cancers harboring cancer stem cells and those resistant to drugs, where a high mitochondrial metabolic rate is observed [13]. Studies are increasingly focusing on the expression levels of key genes involved in cuproptosis and their correlation with tumor prognosis, emphasizing the importance of understanding this link for future therapeutic strategies. This review embarks on an in-depth exploration of the dual role of copper within biological systems—essential for various cellular functions yet potentially harmful when dysregulated. We traverse the landscape of copper metabolism and homeostasis, laying the groundwork for understanding how aberrations in these processes © 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. Feng et al. Cell Communication and Signaling (2024) 22:249 contribute to cancer development. The elucidation of cuproptosis molecular mechanisms presents an evident contrast to traditional cell death pathways, underscoring its unique influence on cancer cell fate (Fig. 1). Further, we dissect the implications of copper dysregulation in the oncogenic process, from tumor initiation to metastasis, and deliberate on the innovative therapeutic strategies targeting this newly discovered cell death form. By integrating insights from translational research and clinical trials, we aim to illuminate the future trajectory of cuproptosis research and its potential to redefine cancer treatment paradigms. Through a synthesis of current knowledge and prospective inquiry, this article endeavors to chart the course for future investigations, poised to unlock the full therapeutic potential of targeting cuproptosis in the fight against cancer. Regulation of copper metabolism and homeostasis in healthy and cancer cells While the critical role of copper metabolism and homeostasis in safeguarding cellular integrity is well documented, the complexity of the dual role of copper — as both a vital nutrient and a potential cellular toxin— underscores the necessity for a nuanced understanding of its metabolic pathways. The intricate balance required to maintain copper homeostasis highlights potential vulnerabilities in cancer cells that could be exploited therapeutically [14–16]. Copper metabolism begins with the absorption of copper from the diet via the gastrointestinal tract, followed by its conveyance to the liver, which acts as a hub for its distribution to various bodily tissues or its integration into enzymatic systems vital for metabolic and protective cellular activities [17, 18]. Copper chaperones play a pivotal role in directing copper to its precise intracellular destinations, facilitating its incorporation Page 2 of 26 into essential enzymes involved in energy metabolism and the mitigation of oxidative stresss [19, 20]. The cellular machinery, including ATPase Copper Transporting Alpha (ATP7A) and ATPase Copper Transporting Beta (ATP7B) transporters, orchestrates the regulation of co (...truncated)