Dissecting copper biology and cancer treatment: ‘Activating Cuproptosis or suppressing Cuproplasia’

Copper, an essential micronutrient, controls multiple fundamental processes throughout all forms of life, such as respiration, cell proliferation and neurotransmitter biosynthesis. High redox activity makes copper a double-edged sword for cell survival, and abnormal copper metabolism is commonly associated with cancer and other diseases. Recently, advances in copper biology have forged new links between researchers from different disciplines to dissect the use of copper targets in cancer treatment. Copper is crucial for maintaining the rapid growth and proliferation of cancer cells, a process known as 'cuproplasia'. However, excess mitochondrial copper accumulation also triggers 'cuproptosis', a new form of programmed cell death, involving the destabilization of Fe-S cluster proteins and the aggregation of DLAT. Accordingly, both activating cuproptosis by copper ionophores and suppressing cuproplasia through copper depletion are noteworthy anticancer options, but this field currently lacks systematic reviews from both biological and chemical perspectives. This review provides a comprehensive overview of the leading known copper biology and copper-targeted cancer therapy, focusing on copper homeostasis, signal transduction, and copper overload/depletion, which should be beneficial for the development of the next-generation of inorganic anticancer drugs. We expect that our review will provide a balanced perspective to the development and comprehension of copper-based cancer therapy.