H2O2 Self-Supplying CaO2 Nanoplatform Induces Ca2+ Overload Combined with Chemodynamic Therapy to Enhance Cancer Immunotherapy

Integrating chemodynamic therapy (CDT) with Ca2+ overload offers a potent strategy for enhancing cancer immunotherapy. However, the effectiveness of this approach is significantly constrained by the scarce availability of H2O2 in solid tumors. Here, we engineered a nanoplatform based on CaO2 nanoparticles (NPs) capable of encapsulating curcumin (CUR) and self-supplying H2O2 for synergistic CDT-augmented antitumor immunotherapy (CaO2@CUR@ZIF-Cu, denoted as CCZC). In the acidic tumor microenvironment, CCZC disintegrated to release CUR and copper(II) ions (Cu2+), revealing the core CaO2 NPs. CDT was amplified by escalating hydroxyl radical (•OH) production through a Fenton-like reaction mediated by H2O2 from the hydrolysis of CaO2 NPs. Ca2+ sourced from CaO2 NPs and CUR, an initiator of Ca2+ overload, induced Ca2+ overload in tumor cells, thereby promoting apoptosis. Subsequently, apoptotic tumor cells released tumor-associated antigens and pro-inflammatory cytokines, triggering adaptive immune responses and enhancing antitumor immunotherapy effects. In vivo experiments demonstrated that the intratumoral administration of CCZC displayed significant inhibitory effects, with an inhibition rate of up to 78% on B16-OVA-tumor-bearing mice compared to untreated. Moreover, an elevated proportion of mature dendritic cells were observed in the tumor-draining lymph nodes, along with an increase in cytotoxic T lymphocytes in the spleen. These findings suggest that our engineered nanoplatform effectively curtailed tumor growth via enhanced cancer immunotherapy by synergizing Ca2+ overload and CDT, proposing a novel strategy for synergistic cancer treatment.