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

Increasing cellular immunogenicity and reshaping the immune tumor microenvironment (TME) are crucial for anti-tumor immunotherapy. Herein, we developed 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 triggers pyroptosis through cascade biocatalysis to boost the immunogenicity of tumor cells, but also remodels the immunosuppressive TME by targeting pyruvate metabolism. By replacing N with weakly electronegative S, we changed the original spatial symmetry of the Cu-N 4 electron distribution and effectively regulated the enzyme-catalyzed process. Compared to spatially symmetric Cu-N 4 single-atom nanozymes (Cu-N 4 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/ATP depletion, triggering pyroptosis and regulating metabolism. This work provides a broad vision for expanding antitumor immunotherapy. This article is protected by copyright. All rights reserved.