Apoptosis and mitochondrial DNA damaged induced by Zn /Ca dual-ions overload for colorectal cancer improved immunotherapy.

Immune checkpoint inhibitor-based cancer immunotherapy has demonstrated significant clinical benefits; however, its efficacy in colorectal cancer (CRC) remains limited owing to insufficient T-cell infiltration into the tumor microenvironment. Notably, therapies targeting mitochondrial dysfunction or stress pathways can activate innate immunity and promote the recruitment of tumor-infiltrating lymphocytes. In this study, we developed ZIF-8 nanoparticles (NPs) mineralized with CaCO to construct ZIF-8@CaCO NPs, designed to enhance tumor cell damage via dual Zn/Ca ion overload. The ZIF-8@CaCO NPs exhibited optimal size distribution, excellent biocompatibility, and the ability to release Zn and Ca ions under mildly acidic conditions, subsequently generating reactive oxygen species. Importantly, an overload of Zn and Ca ions combined with oxidative stress disrupted mitochondrial homeostasis, leading to the release of oxidized mitochondrial DNA. This process stimulated innate immune responses, including a direct anti-tumor effect and the recruitment of CD8 T cells. Additionally, the released mtDNA enhanced cross-presentation in dendritic cells, further amplifying the anti-tumor immune response. Our findings indicate that ZIF-8@CaCO NPs hold great promise for improving immunotherapeutic outcomes in CRC.