Zinc Ion-Induced Immune Responses in Antitumor Immunotherapy

Zinc has emerged as a crucial metal in the field of antitumor immunotherapy. Despite its recognized significance, the specific molecular mechanisms behind zinc ion -mediated antitumor immune responses remain inadequately elucidated. Herein, we present a comprehensive analysis of the effects of zinc ions on immune regulation in antitumor immunotherapy. Zinc ions overload within tumor cells results in the generation of reactive oxygen species (ROS) through two mechanisms: the leakage of electrons from aerobic respiration in mitochondria and the oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) by NADPH oxidase 1 (NOX1). The accumulation of ROS and the resulting damage to mitochondrial DNA (mtDNA) activate multiple signaling pathways, leading to the production of high levels of interferons and inflammatory cytokines. Besides, excessive zinc ions induce tumor cell pyroptosis through two pathways: the caspase-1/ GSDMD-dependent canonical pathway and the caspase-3/GSDME-dependent alternative pathway, leading to the exposure of many damage -associated molecular patterns (DAMPs). As a result, strong systemic antitumor immunity is triggered, leading to the inhibition of tumor growth. This study unveils the intricate network of signaling pathways mediated by zinc ions in the tumor microenvironment (TME). Such findings not only lay a solid foundation for the development of zinc -based antitumor drugs but also advance the field of zinc -based metalloimmunotherapy.