Metal-Based Nanomedicines for Inducing Programmed Cell Death to Enhance the Efficacy of Cancer Immunotherapy

Metal ions exert indispensable functions in various physiological processes, and metal ion homeostasis is needed in cells. Intracellular metal ion homeostasis is regulated by their efflux and influx across the cell membrane. Dysregulation of intracellular metallic ions can trigger programmed cell death (PCD). In recent years, metallic ions as potent immunomodulators and enhancers for cancer immunotherapy through modulating the immunosuppressive tumor microenvironment and triggering an immunostimulatory response have been extensively explored. The review focuses on the mechanism of PCD and immunomodulatory effects for various metal ions including iron, copper, calcium, zinc, and manganese, and provides a systematic overview of nanoparticles for delivering metallic ions or constructed of metals to realize PCD and enhance cancer immunotherapy. Finally, the prospect and challenges of clinic translation of metal-based nano-drug delivery systems in cancer therapy are outlined, and especially restriction of large-scale manufacturing and safety concern for clinic translation are further discussed.