Copper, cuproptosis, and cancer: biology concepts of a novel cell death

Abstract

Copper is an essential trace element required for mitochondrial respiration, redox regulation, iron metabolism, and cellular signalling, but excessive or mislocalised copper can be cytotoxic. Cuproptosis is a recently identified form of regulated cell death in which copper binds to lipoylated mitochondrial proteins, promotes their aggregation, destabilises iron–sulfur cluster proteins, and induces mitochondrial proteotoxic stress. Copper therefore has context-dependent roles in cancer. Physiological copper supports tumour metabolism, angiogenesis, extracellular-matrix remodelling, and selected oncogenic signalling pathways, whereas therapeutic copper depletion can inhibit copper-dependent tumour processes. Conversely, copper ionophores and related approaches may increase intracellular copper sufficiently to induce cuproptosis in metabolically susceptible cancer cells. This review describes systemic and intracellular copper homeostasis, including intestinal absorption, intracellular trafficking, mitochondrial copper distribution, storage, and export. Particular attention is given to CTR1/SLC31A1, the functionally distinct copper-transporting ATPases ATP7A and ATP7B, metallothioneins, copper chaperones, and cytochrome c oxidase assembly factors. We also examine how cancer cells reprogramme copper handling to support proliferation, angiogenesis, metastasis, and immune evasion. Finally, we discuss the molecular basis of cuproptosis, including the roles of FDX1, FDXR, LIAS, DLAT, mitochondrial respiration, protein lipoylation, and iron–sulfur cluster destabilisation. Current evidence indicates that cuproptosis susceptibility varies among tumour types and depends on copper handling, mitochondrial metabolic state, and the integrity of the protein-lipoylation machinery. Defining these determinants will be necessary for the development of tumour-selective copper-targeted therapies.