Cu-related agents for cancer therapies

As an indispensable micronutrient, copper (Cu) plays an important role in promoting metabolism and maintaining various basic biological functions. Copper homeostasis in the human body is tightly regulated and the imbalance of copper levels can lead to metabolic abnormalities and toxic effects on cells. Hence, Cu-related agents have sparked tremendous attention in the field of cancer therapy. Two copper-related strategies have been proposed for the treatment of tumors: depleting copper inside tumors to inhibit proliferation, and providing excess copper to promote cell apoptosis or cuproptosis. Correspondingly, copper depletors are adopted to reduce copper bioavailability, and a variety of copper-based agents, including copper-based nanosystems, copper complexes and nano-copper complexes, are applied to supplement copper. This review systematically summarizes the recent development of Cu-related agents for cancer therapies from the perspective of copper depletion and copper supplementation. Considering the large number of agents used to supply copper, copper-based nanosystems, copper complexes and nano-copper complexes are discussed in separate sections. Finally, the challenges and the future developments of Cu-related anticancer agents are explored to provide some enlightenment for future research.