A Pyroptosis-Inducing Arsenic(III) Nanomicelle Platform for Synergistic Cancer Immunotherapy

Immunogenic cell death (ICD) could activate anti-tumor immune responses, which is highly attractive for improving cancer treatment effectiveness. Here, this work reports a multifunctional arsenic(III) allosteric inhibitor Mech02, which induces excessive accumulation of ¹O₂ through sensitized biocatalytic reactions, leading to cell pyroptosis and amplified ICD effect. After Mech02 is converted to Mech03, it could actualize stronger binding effects on the allosteric pocket of pyruvate kinase M2, further interfering with the anaerobic glycolysis pathway of tumors. The enhanced DNA damage triggered by Mech02 and the pyroptosis of cancer stem cells provide assurance for complete tumor clearance. In vivo experiments prove nanomicelle Mech02-HA NPs is able to activate immune memory effects and raise the persistence of anti-tumor immunity. In summary, this study for the first time to introduce the arsenic(III) pharmacophore as an enhanced ICD effect initiator into nitrogen mustard, providing insights for the development of efficient multimodal tumor therapy agents.