Potent Zinc(II)-Based Immunogenic Cell Death Inducer Triggered by ROS-Mediated ERS and Mitochondrial Ca²⁺ Overload

Zn1 and Zn2 are Zn-based complexes that activate the immunogenic cell death (ICD) effect by Ca²⁺-mediated endoplasmic reticulum stress (ERS) and mitochondrial dysfunction. Compared with Zn1, Zn2 effectively caused reactive oxidative species (ROS) overproduction in the early phase, leading to ERS response. Severe ERS caused the release of Ca²⁺ from ER to cytoplasm and further to mitochondria. Excessive Ca²⁺ in mitochondria triggered mitochondrial dysfunction. The damage-associated molecular patterns (DAMPs) of CRT, HMGB1, and ATP occurred in T-24 cells exposed to Zn1 and Zn2. The vaccination assay demonstrated that Zn1 and Zn2 efficiently suppressed the growth of distant tumors. The elevated CD8⁺ cytotoxic T cells and decreased Foxp3⁺ cells in vaccinated mice supported our conclusion. Moreover, Zn1 and Zn2 improved the survival rate of mice compared with oxaliplatin. Collectively, our findings provided a new design strategy for a zinc-based ICD inducer via ROS-induced ERS and mitochondrial Ca²⁺ overload.