Cuproptosis: A Review on Mechanisms, Role in Solid and Hematological Tumors, and Association with Viral Infections

Abstract

Cuproptosis is a distinct modality of regulated cell death precipitated by an overload of intracellular copper, critically dependent on mitochondrial respiration. The underlying mechanism involves the direct interaction of copper ions with lipoylated components integral to the mitochondrial tricarboxylic acid (TCA) cycle. This binding event triggers the aggregation of these proteins, induces significant proteotoxic stress, and leads to the depletion of essential iron-sulfur cluster proteins, culminating in cell demise. Given that copper homeostasis is frequently dysregulated within cancer cells, rendering them potentially more susceptible to copper-induced toxicity, cuproptosis has rapidly become a focal point of oncological research. This systematic review meticulously analyzes and synthesizes findings from a curated collection of 45 research articles. It aims to provide a comprehensive description of the molecular intricacies of cuproptosis, explore its documented associations with a spectrum of solid tumors (including gastric, lung, liver, neuroblastoma, and ovarian cancers) and lymphoma, and examine its emerging connections with viral infections like COVID-19 and pseudorabies virus. The review elaborates on the reported prognostic significance of cuproptosis-related genes and associated pathways across various malignancies. Furthermore, it details the burgeoning therapeutic strategies designed to harness cuproptosis, encompassing the application of copper ionophores, the development of sophisticated nanomedicine platforms, and synergistic approaches that combine cuproptosis induction with immunotherapy, chemotherapy, or sonodynamic therapy. The potential clinical utility of cuproptosis-associated biomarkers for predicting patient prognosis and therapeutic response is discussed based on the evidence presented in the reviewed literature.

Keywords: Cuproptosis; Lymphoma; Solid tumors.

Figure 1

The figure illustrates the cellular mechanism of cuproptosis, a copper-induced cell death pathway. Copper enters cells via CTR1, is reduced by STEAP, and is trafficked by chaperones like ATOX1, CCS, and COX17 to destinations including the mitochondria. Excess Cu⁺ binds to lipoylated DLAT in the mitochondria, causing protein aggregation, Fe-S cluster loss, and proteotoxic stress. Elesclomol enhances this process, while MT, GSH, and transcription factors like Nrf2 help regulate copper levels. Cuproptosis is especially relevant in cancer cell metabolism. ES Elesclomol; STEAP Six-transmembrane epithelial antigen of the prostate; CTR1 Copper transporter 1; CCS Copper chaperone for superoxide dismutase; ATOX1 Antioxidant 1 copper chaperone; COX17 Cytochrome c oxidase copper chaperone; SOD1 Superoxide dismutase 1; MT Metallothioneins; GSH Glutathione; COA6 Cytochrome c oxidase assembly factor 6; SCO1/2 Synthesis of cytochrome c oxidase; COX Cytochrome c oxidase; MTF-1 Metal Regulatory Transcription Factor 1; Nrf2 Nuclear factor erythroid 2-related factor 2; SLC25A3 Solute carrier family 25 member 3; ATP7A/B ATPase copper transporting alpha/beta.