Copper homeostasis and cuproptosis in tumor biology: mechanistic insights and clinical perspectives.

Copper is considered a necessary trace element that plays crucial roles in energy production in mitochondria, redox regulation, and metabolism. Copper homeostasis disturbance may promote tumor initiation and progression and therapy resistance. Cuproptosis is a regulated form of cell death when mitochondrial copper interacts with the proteins from the citric acid cycle causing their oligomerization and aggregation, loss of Fe-S proteins, proteotoxic stress, and cell death. Unlike apoptosis, ferroptosis, and necroptosis, cuproptosis can be promoted in cells keeping functioning lipoylation of proteins and actively using mitochondrial oxidative metabolism. Copper also influences tumor-related signaling pathways, induces angiogenesis, invasion, metabolic rewiring, and tumor immunity. This review summarizes copper homeostasis and cuproptosis, possible biomarkers, and connections between cuproptosis and other types of regulated cell death. In addition, it concerns copper chelators, ionophores, targeted nanotherapy with high copper content, the combination of copper therapy with chemotherapy, radiotherapy, and immunotherapy and it presents recent clinical data on the therapeutic effect of copper agents.