Programmed Targeting Pyruvate Metabolism Therapy Amplified Single‐Atom Nanozyme‐Activated Pyroptosis for Immunotherapy

Abstract Increasing cellular immunogenicity and reshaping the immune tumor microenvironment (TME) are crucial for antitumor immunotherapy. Herein, this work develops a novel single‐atom nanozyme pyroptosis initiator: UK5099 and pyruvate oxidase (POx)‐co‐loaded Cu‐NS single‐atom nanozyme (Cu‐NS@UK@POx), that not only trigger pyroptosis through cascade biocatalysis to boost the immunogenicity of tumor cells, but also remodel the immunosuppressive TME by targeting pyruvate metabolism. By replacing N with weakly electronegative S, the original spatial symmetry of the Cu‐N₄ electron distribution is changed and the enzyme‐catalyzed process is effectively regulated. Compared to spatially symmetric Cu‐N₄ single‐atom nanozymes (Cu‐N₄ SA), the S‐doped spatially asymmetric single‐atom nanozymes (Cu‐NS SA) exhibit stronger oxidase activities, including peroxidase (POD), nicotinamide adenine dinucleotide (NADH) oxidase (NOx), L‐cysteine oxidase (LCO), and glutathione oxidase (GSHOx), which can cause enough reactive oxygen species (ROS) storms to trigger pyroptosis. Moreover, the synergistic effect of Cu‐NS SA, UK5099, and POx can target pyruvate metabolism, which not only improves the immune TME but also increases the degree of pyroptosis. This study provides a two‐pronged treatment strategy that can significantly activate antitumor immunotherapy effects via ROS storms, NADH/glutathione/L‐cysteine consumption, pyruvate oxidation, and lactic acid (LA)/ATP depletion, triggering pyroptosis and regulating metabolism. This work provides a broad vision for expanding antitumor immunotherapy.