Zinc dyshomeostasis: an emerging hallmark of cancer

Abstract Zinc is an essential trace metal in the human body, playing a crucial role in various biological processes. It exists in 2 forms in cells: “bound” and “labile,” depending on its affinity with ligands. Zinc homeostasis is tightly regulated by zinc transporters, including the ZIP and ZnT protein families. However, zinc dyshomeostasis has been observed in various cancers, including breast cancer, pancreatic cancer, and hepatocellular carcinoma. Recent studies indicate that the zinc content in blood and tumor tissues can either increase or decrease, whereas specific zinc transporters may be upregulated or downregulated. Zinc dysregulation in cancer cells, as well as in immune cells and non-immune stromal cells, potentially affects the cell cycle, apoptosis, metabolism, immunity, and treatment resistance. Although many reviews have discussed zinc homeostasis under physiological conditions, few have explores its role in cancer pathology. We conducted a literature search on PubMed and Google Scholar using the keywords “tumor,” “zinc levels,” and “zinc transporter,” excluding outdated articles and those lacking full-text access. Among similar studies, we selected articles with more recent publication dates and larger sample sizes. In this review, we summarize recent advances in the study of zinc in tumors, highlighting studies on abnormal zinc levels and zinc transporters in various cancers. We also explore the effects of zinc dysregulation, its potential mechanisms, and the emerging concept that zinc dyshomeostasis may be a hallmark of cancer.