Potent Zinc(II)-Based Immunogenic Cell Death Inducer Triggered by ROS-Mediated ERS and Mitochondrial Ca 2+ Overload.

Zn1 and Zn2 are Zn-based complexes that activate the immunogenic cell death (ICD) effect by Ca 2+ -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 Ca 2+ from ER to cytoplasm and further to mitochondria. Excessive Ca 2+ 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 Ca 2+ overload.