Core–shell structural calcium-deposited manganese-copper oxide that induces immunogenic cell death and STING activation for augmented metalloimmunotherapy of triple-negative breast cancer

Metal ions mediated tumor immunotherapy showed considerable potential in clinical application, but the efficacy of single metal ion elicited immune response was relatively low. Herein, we developed a PDGFB cyclopeptide modified core–shell structural calcium-deposited manganese-copper oxide (CMC) for enhanced metalloimmunotherapy of triple-negative breast cancer. Due to the overexpression of PDGFR-β receptors, PCMC selectively recognised 4T1 cells, efficiently entering the tumor cells and triggering the release of substantial amounts of Cu, Mn, and Ca ions. These Cu ions catalysed Fenton-like reactions, rapidly increasing intracellular ROS levels, thereby inducing cuproptosis in tumor cells and promoting calreticulin exposure and HMGB1 release with confirmed ICD. Additionally, Mn ions activated the cGAS-STING signalling pathway, enhancing dendritic cell (DC) maturation, promoting cytotoxic T lymphocyte (CTL) infiltration, and boosting the anti-tumor immune response. Ca ions disrupted intracellular calcium homeostasis, synergistically enhancing ROS production and potentiating cGAS-STING activation, further amplifying the anti-tumor immunotherapy. In vitro and organoid assays confirmed that PCMC-mediated ROS production effectively induced tumor cuproptosis and calreticulin exposure and HMGB1 release. In vivo, PCMC markedly promoted DC maturation, increased CTL infiltration, and facilitated NK cell recruitment, leading to significant inhibition of tumor growth, recurrence, and metastasis. This study presents a novel and practical strategy for developing polymetallic-based anti-tumor immunotherapies.