Coordination engineering of FeCo dual single-atom nanozymes with photothermal-enhanced cascaded catalysis for efficient pancreatic cancer immunotherapy

Cancer immunotherapy holds great promise in improving therapeutic outcomes. However, its effectiveness is significantly hindered by the inadequate immunogenicity and potent immuno-suppressive nature of the tumor microenvironment (TME). Herein, we elaborately design an advanced iron-cobalt dual-single-atom nanozyme (FeCo-DA) with adjacent Fe-N/O-C and Co-N/O-C pair sites. This design aims to induce potent immunogenic cell death (ICD), ultimately enhancing cancer immunotherapy by activating the immune microenvironment. Compared to Fe and Co single-atom nanozyme, FeCo-DA demonstrated superior photothermal effects and cascaded catalytic performance by simultaneously mimicking peroxidase (POD), catalase (CAT), and glutathione oxidase (GSH-OXD). The cascaded catalysis not only augmented oxidative stress but also exacerbated the redox imbalance through sustainable generation of hydroxyl radicals (∙OH) and depletion of glutathione (GSH). The comprehensive in vitro and vivo experiments demonstrated that FeCo-DA effectively induced immunogenic cell death (ICD) by releasing damage-associated molecular patterns (DAMPs). The photothermal-enhanced cascaded catalytic therapy exhibited remarkable therapeutic effects on a mouse model of pancreatic cancer. This work highlights the potential of structure engineering in enhancing the efficacy of dual single-atom nanozyme for ICD-based cancer immunotherapy.