Cope with copper: From copper linked mechanisms to copper-based clinical cancer therapies

Recent studies have established a strong link between copper and cancer biology, as copper is necessary for cancer growth and metastasis. Beyond the conventional concept of copper serving as a catalytic cofactor of metalloenzymes, emerging evidence demonstrates copper as a regulator for signaling transduction and gene expression, which are vital for tumorigenesis and cancer progression. Interestingly, strong redox-active properties make copper both beneficial and detrimental to cancer cells. Cuproplasia is copper-dependent cell growth and proliferation, whereas cuproptosis is copper-dependent cell death. Both mechanisms act in cancer cells, suggesting that copper depletion and copper supplementation may be viable approaches for developing novel anticancer therapies. In this review, we summarized the current understanding of copper's biological role and related molecular mechanisms in cancer proliferation, angiogenesis, metastasis, autophagy, immunosuppressive microenvironment development, and copper-mediated cancer cell death. We also highlighted copper-based strategies for cancer treatment. The current challenges of copper in cancer biology and therapy and their potential solutions were also discussed. Further investigation in this field will yield a more comprehensive molecular explanation for the causal relationship between copper and cancers. It will reveal a series of key regulators governing copper-dependent signaling pathways, thereby providing potential targets for developing copper-related anticancer drugs.