Zinc-Doped Calcium Phosphate Nanoagonists Amplifies cGAS-STING Signaling for Boosting Pyroptosis-Induced Cancer Immunotherapy

The combination of chemotherapy and immunotherapy represents a promising approach that leverages their complementary benefits. However, the side effects resulting from off-target effects and the low efficiency of immune activation remain a significant concern. Herein, we developed a zinc-doped calcium phosphate (ZCP) nanocarrier for the delivery of the chemotherapeutic drug doxorubicin (DOX). By further encapsulating whole proteins from 4T1 breast cancer cells, we constructed a novel nanodrug delivery system named ZCPDM. This system enables specific targeting of tumor cells and undergoes intracellular degradation to release DOX, Zn2+, and Ca2+. As a chemotherapeutic agent, DOX induces apoptosis while significantly elevating intracellular reactive oxygen species (ROS), thereby enhancing cytotoxicity. This leads to DNA damage and the release of chromosomal fragments. These DNA fragments, together with Zn2+, activate the cGAS-STING signaling pathway and trigger pyroptosis, which promotes more efficient recognition and clearance of tumor cells by the immune system. Through these dual mechanisms, ZCPDM effectively combines chemotherapy and immunotherapy. The anti-tumor efficacy and underlying mechanisms were validated at the cellular level. Furthermore, studies in tumor-bearing mice demonstrated its robust anti-tumor performance and ability to suppress tumor recurrence, along with good biosafety. This targeted drug delivery system achieves safe and synergistic chemo-immunotherapy through homologous targeting-mediated pyroptosis and activation of the cGAS-STING pathway, offering a novel and promising strategy for cancer treatment.