Targeting cuproptosis for cancer therapy: Focus on the anti-tumor immune system

Abstract

Copper (Cu) is an indispensable micronutrient that maintains signaling pathways and biological homeostasis in almost all cell types; however, its excess affects the tricarboxylic acid cycle, causes the accumulation of fatty acylated proteins, destabilization of iron-sulfur cluster proteins, and increases the levels of intracellular reactive oxygen species, leading to proteotoxic stress and cell death. Cuproptosis, a form of Cu-dependent cell death, differs from other types of regulated cell death (RCD) and was first reported in Science in 2022. Recently, the RCD pathways have been targeted in cancer therapy. However, the escape of apoptosis in tumor cells causes resistance to treatment and tumor recurrence. Therefore, there is an urgent need to study the alternative mechanisms of cancer cell mortality. Compared to normal patients, a significant increase in serum Cu ion levels has been observed in patients with tumors. Moreover, tumor cell proliferation, angiogenesis, and metastasis are associated with cuproptosis. Thus, exploring cancer signaling pathways related to cuproptosis will provide a new perspective for the development of anti-cancer drugs. Importantly, cuproptosis is closely associated with the modulation of anti-tumor immunity. The expression of cuproptosis-related genes (CRGs) is significantly correlated with immune cell infiltration and the immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1). Based on these findings, a series of cuproptosis-related drugs have been used in tumor-targeted combination therapy or as immune synergists. Therefore, elucidating the role of cuproptosis per cancer stage and in the tumor immune microenvironment (TIME) is helpful in clarifying the potential value of Cu in the treatment of specific cancers. In this review, we summarize specific cancer signaling pathways related to cuproptosis and cancer treatment based on the regulation of Cu concentration. The combination of these two approaches may help researchers develop more therapies targeting cuproptosis-related pathways. Importantly, we focused on the effect of cuproptosis on the TIME and systematically discussed the role of CRGs in tumor immunity considering CRG-related anti-tumor immune signaling pathways, tumor prognosis scoring system, anti-tumor immunotherapy, and biological experiments and bioinformatics prediction models, to provide new ideas for the development of anticancer therapy targeting cuproptosis-related pathways.

Keywords: Copper homeostasis; Cuproptosis; Drug synergism; Immunotherapy.

Graphical abstract

Figure 1

Mechanism of cuproptosis. Cuproptosis is a distinct form of cell death triggered by copper (Cu)-ion imbalance. Cu ions are transported into the cell and reduced to Cu⁺ by FDX1, resulting in the aggregation of DLAT, a vital enzyme in the TCA cycle. This aggregation disrupts the TCA cycle and electron transport chain (ETC), leading to mitochondrial dysfunction and increased reactive oxygen species (ROS) production. Depletion of reduced glutathione (GSH) and disturbance of iron–sulfur (Fe–S) clusters exacerbate oxidative stress, further contributing to cuproptosis. The diagram also highlights the role of STEAP proteins in Cu transport and the interplay between cuproptosis and other cell death pathways, such as ferroptosis and apoptosis. Maintaining Cu homeostasis is crucial for cellular health. ATP7A: ATPase copper transporting alpha; ATP7B: ATPase copper transporting beta; CTR1: Copper transporter 1; Cu: Copper; DLAT: Dihydrolipoamide S-acetyltransferase; ETC: Electron transport chain; FDX1: Ferredoxin 1; Fe–S: Iron–sulfur; GSH: Glutathione; GSSG: Glutathione disulfide; LA: Lipoic acid; LIAS: Lipoic acid synthetase; NADP: Nicotinamide adenine dinucleotide phosphate; NADPH: Nicotinamide adenine dinucleotide phosphate; ROS: Reactive oxygen species; STEAP: Six transmembrane epithelial antigen of prostate; TCA: Tricarboxylic acid.

Figure 2

Cancer signaling pathway related to Cu and CRGs. Copper (Cu) regulates the secretion of angiogenic factors and indirectly influences their activity. Cu chaperones can also influence tumor angiogenesis. Cu can influence tumor growth by regulating the MAPK signaling pathway or by influencing the autophagic pathway. Some CKGs, such as CTR1, ATP7A, and ATP7B, are associated with resistance to tumor chemotherapy. CKGs and Cu can also influence PD-1/PD-L1 expression and TIME. Therefore, targeting all these cancer pathways through the application of Cu-related drugs may be a new approach for cancer treatment. ATOX1: Antioxidant 1 Cu chaperone; ATP7A: ATPase copper transporting alpha; ATP7B: ATPase copper transporting beta; CKGs: Cuproptosis key genes; CSL: citrate synthase like; CTR1: Copper transporter 1; Cu: Copper; ERK: Extracellular signal-regulated kinase; EMT: Epithelial-mesenchymal transition; FAK: Focal adhesion kinase; Hey: Hairy/E(spl)-related with YRPW motif; Hes1/5: Xxx; HIF-1: Hypoxia-inducible factor 1; IKT: Invariant natural killer T cell; IL: Interleukin; LOX: Lysyl oxidase; LOXL: Lysyl oxidase-like; LTPT1: Lipolytransferase 1; MAPK: Mitogen-activated protein kinase; MEK: Mitogen-activated protein kinase kinases; NF-κB: Nuclear factor-κB; NICD: Notch1 intracellular domain; P62-SQSTM1: The p62 protein or sequestosome 1; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; PI3K: Phosphatidylinositol-4,5-bisphosphate 3-kinase; PreTα: prothymosin alpha; RAS: Rat sarcoma; ROS: Reactive oxygen species; SRC: A proto-oncogene tyrosine-protein kinase; TIME: Tumor immune microenvironment; ULK: Unc-51 like autophagy activating kinase; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; VSMC: Vascular smooth muscle cell.