Artificial Induction of Mitochondrial Calcification as a Trigger for Cancer Immunotherapy.

Tumor calcification shows promise as a clinical predictor of tumor response and often involves mitochondrial calcification, which provides mineral precursors for extracellular deposition. However, the methods available for regulating mitochondrial calcification in tumor calcification therapy are limited. Herein, we designed and synthesized (4-carboxybutyl) triphenylphosphonium bromide (CTPP)-functionalized calcium peroxide (CaO2) nanoparticles (CTPP/CaO2) to achieve selective induction of mitochondrial calcification in hepatocellular carcinoma cells. The CTPP/CaO2-induced mitochondrial calcification sustains elevated intracellular calcium ion (Ca2+) and reactive oxygen species (ROS), exacerbates mitochondrial dysfunction, and triggers tumor cell death via pyroptosis. Pyroptosis further promotes the release of intracellular contents and exposure of calreticulin on the cell membrane, effectively activating the antitumor immune response in vivo. This mitochondrial calcification strategy integrates direct killing of tumor cells with subsequent activation of the antitumor immune response, thus providing a promising approach for engineering mitochondrial calcification with potential applications in cancer therapy. STATEMENT OF SIGNIFICANCE: Tumor calcification is a promising anticancer therapeutic strategy, but most existing methodologies are confined to non-specific extracellular mineralization with unsatisfactory targeting precision. We herein report a mitochondria-targeted nanoplatform that selectively initiates mitochondrial calcification against hepatocellular carcinoma. The resultant mitochondrial impairment and persistent ROS overproduction drive tumor pyroptosis, enabling direct tumor ablation and robust antitumor immune activation. Meanwhile, in situ tumor calcification augments CT/MR imaging contrast. This mitochondria-targeted calcification strategy achieves integrated theranostics and provides a potential strategy for refractory solid malignancies.