Intracellular metal ion-based chemistry for programmed cell death

Intracellular metal ions play essential roles in multiple physiological processes, including catalytic action, diverse cellular processes, intracellular signaling, and electron transfer. It is crucial to maintain intracellular metal ion homeostasis which is achieved by the subtle balance of storage and release of metal ions intracellularly along with the influx and efflux of metal ions at the interface of the cell membrane. Dysregulation of intracellular metal ions has been identified as a key mechanism in triggering programmed cell death (PCD). Despite the importance of metal ions in initiating PCD, the molecular mechanisms of intracellular metal ions within these processes are infrequently discussed. An in-depth understanding and review of the role of metal ions in triggering PCD may better uncover novel tools for cancer diagnosis and therapy. Specifically, the essential roles of calcium (Ca²⁺), iron (Fe^2+/3+), copper (Cu^+/2+), and zinc (Zn²⁺) ions in triggering PCD are primarily explored in this review, and other ions like manganese (Mn^2+/3+/4+), cobalt (Co^2+/3+) and magnesium ions (Mg²⁺) are briefly discussed. Further, this review elaborates on the underlying chemical mechanisms and summarizes these metal ions triggering PCD in cancer therapy. This review bridges chemistry, immunology, and biology to foster the rational regulation of metal ions to induce PCD for cancer therapy.