Targeting Copper in Cancer: Chelators to Counteract Cuproplasia and Ionophores to Promote Cuproptosis

Precise copper homeostasis is vital for cellular physiology, and its dysregulation is closely linked to several pathological conditions. Within oncology, copper exerts a dual role. On the one hand, cellular copper is essential for promoting tumor growth and progression (cuproplasia). On the other hand, the accumulation of intracellular copper can induce cytotoxicity and regulated cell death (cuproptosis). Consequently, therapeutic strategies that either utilize chelators to inhibit cuproplasia or employ ionophores to induce cuproptosis are emerging as innovative anticancer approaches. Despite several compounds entering clinical trials, copper-targeted drug discovery remains underexploited due to incompletely elucidated molecular pathways and a lack of ligands with highly specific mechanisms of action. This Perspective provides a summary of the role of copper in cancer and furnishes an updated overview of ligands used to modulate cellular copper levels, detailing their structural, chemical, and biological properties, while outlining future directions for drug discovery in this field.