Revealing the Mutually Enhanced Mechanism of Necroptosis and Immunotherapy Induced by Defect Engineering and Piezoelectric Effect

Abstract Owing to low immunogenicity‐induced immune escape and short‐term circulating immune responses, the efficiency of immunotherapy is unsatisfactory. Therefore, triggering immunogenic cell death and establishing a long‐term, mutually reinforced treatment modality are urgent challenges. In this study, ultrathin CaBi₂Nb₂O₉ nanosheets with tunable oxygen vacancies (abbreviated as CBNO‐OV1) are prepared for synergistic necroptosis and immunotherapy. The optimized vacancy concentration significantly improves the piezoelectric effect under ultrasound irradiation, thereby considerably improving the generation of reactive oxygen species (ROS). Density functional theory shows that oxygen vacancies can improve the efficiency of electron hole separation by suppressing their recombination, thus resulting in enhanced piezocatalytic activity. Moreover, the piezoelectric effect improves the permeability of tumor cell membranes, thus resulting in Ca²⁺ influx. Additionally, CBNO‐OV1 also releases a portion of Ca²⁺, which induces necroptosis assisted by explosive ROS. Ribonucleic acid transcription tests suggest the mechanisms associated with immune response activation and necroptosis. More importantly, necroptosis can trigger a significant immune response in vivo, thus activating macrophage M1 polarization through the NF‐kappa B pathway and promoting T‐cell differentiation.Tumor Necrosis Factor‐α differentiated from macrophages conversely promotes necroptosis, thus realizing a mutually enhanced effect. This study demonstrates the feasibility of mutually reinforced necroptosis and immunotherapy for amplifying tumor efficacy.