Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives

Zhang et al. Journal of Hematology & Oncology (2024) 17:68 https://doi.org/10.1186/s13045-024-01589-8 Journal of Hematology & Oncology Open Access REVIEW Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives Chenliang Zhang1*†, Tingting Huang2† and Liping Li3 Abstract Cuproptosis is a newly identified form of cell death induced by excessive copper (Cu) accumulation within cells. Mechanistically, cuproptosis results from Cu-induced aggregation of dihydrolipoamide S-acetyltransferase, correlated with the mitochondrial tricarboxylic acid cycle and the loss of iron–sulfur cluster proteins, ultimately resulting in proteotoxic stress and triggering cell death. Recently, cuproptosis has garnered significant interest in tumor research due to its potential as a crucial therapeutic strategy against cancer. In this review, we summarized the cellular and molecular mechanisms of cuproptosis and its relationship with other types of cell death. Additionally, we reviewed the current drugs or strategies available to induce cuproptosis in tumor cells, including Cu ionophores, small compounds, and nanomedicine. Furthermore, we targeted cell metabolism and specific regulatory genes in cancer therapy to enhance tumor sensitivity to cuproptosis. Finally, we discussed the feasibility of targeting cuproptosis to overcome tumor chemotherapy and immunotherapy resistance and suggested future research directions. This study suggested that targeting cuproptosis could open new avenues for developing tumor therapy. Keywords Copper, Cuproptosis, Cancer, Tumor therapy, Drug resistance, Tumor immunotherapy Introduction Copper (Cu) is an essential trace metal element for normal physiological functions primarily obtained from dietary supplements. In biological systems, Cu exists predominantly in two oxidative states: divalent copper ions (Cu2+) and monovalent copper ions (Cu+). Cu+ is the principal oxidative form and plays a significant role † Chenliang Zhang and Tingting Huang contributed equally to this work. *Correspondence: Chenliang Zhang 1 Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center and Laboratory of Molecular Targeted Therapy in Oncology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, People’s Republic of China 2 Division of Abdominal Cancer, Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China 3 Department of Pharmacy, Chengdu Fifth People’s Hospital, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China in physiological and pathological regulation within cells [1–3]. Disruptions in Cu homeostasis can induce disease onset; for instance, Cu overload may lead to Wilson’s disease [4], while Cu deficiency can cause Menkes disease [5]. Furthermore, previous studies have demonstrated that Cu could promote tumor cell proliferation, angiogenesis, and metastasis and reduces the efficacy of tumor treatments [6]. However, excess Cu in the cells can also cause cellular damage. Researchers observed that using Cu ionophores to elevate Cu levels within tumor cells could cause cell death [7, 8]. Although subsequent studies have extensively investigated the molecular mechanisms underlying Cu-induced cell death, such as the association of this type of cell death with reactive oxygen species (ROS), apoptosis, and ferroptosis-related signaling pathways, the key mechanisms remain unclear. Tsvetkov et al. termed the Cu-induced cell death cuproptosis in 2022 based on their findings that this form of cell death depends on the aggregation of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and the reduction of iron–sulfur cluster (Fe–S) © The Author(s) 2024. 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To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. Zhang et al. Journal of Hematology & Oncology (2024) 17:68 proteins, triggered by Cu accumulation in mitochondria, leading to proteotoxic stress, and cell death [9]. With the concept and mechanism of cuproptosis established, researchers have increasingly focused on cuproptosis in cancer therapy and demonstrated that Cu-based treatments play a pivotal role in inhibiting tumor growth. In this review, we summarized the core molecular mechanisms of cuproptosis and discussed the relationship between it and other forms of cell death. Moreover, we systematically summarized the current understanding of targeting cuproptosis for tumor therapy, including using Cu ionophores, small compounds, and nanomedicine to induce cuproptosis and targeting cell metabolism or certain genes to sensitize cuproptosis. Additionally, we discussed the potential of targeting cuproptosis to overcome tumor drug resistance in chemotherapy, targeted therapy, and immunotherapy. We also discussed the opportunities and challenges in targeting cuproptosis-associated cancer therapy. Cu metabolism Cu homeostasis is essential for the normal physiological functioning of human life. In humans, Cu uptake, distribution, transport, and elimination are meticulously regulated (Fig. 1A), which is crucial to prevent deficiency or excessive Cu accumulation in various tissues and cells, thereby averting disease onset [10]. Humans predominantly acquire Cu through their diet, with an adult daily requirement ranging from 0.8 to 2.4 mg [3]. Following digestion in the stomach and duodenum, Cu is primarily absorbed in the small intestine, where C u2+ is reduced + to Cu by metalloreductases, such as six-transmembrane epithelial antigen of the prostate (STEAP) [11] and duodenal cytochrome b (DCYTB) [12], before being transported into enterocytes by Cu transport protein 1 (CTR1), also known as the solute carrier family 31 member 1 (SLC31A1) [13], located at the apical membrane of enterocytes. Subsequently, Cu is exported to the interstitial fluid or bloodstream by the protein ATPase copper transporting alpha (ATP7A) [14]. Cu in the bloodstream usually binds to plasma proteins, such as ceruloplasmi (...truncated)