Sonocatalytic therapy is gaining interest for its non-invasive nature, precise control, and excellent tissue penetration, making it a promising approach for treating malignant tumors. While defect engineering enhances electron and hole separation to boost reactive oxygen species (ROS) generation, challenges in constructing effective hole traps compared to electron traps severely limit ROS production. In this study, 2D ZnIn2S4-VIn nanosheets enriched are rationally designed with In vacancies for the efficient capture of electrons and holes, which has achieved substantial sonocatalytic performance in suppressing tumor growth. Compared to pristine ZnIn2S4 nanosheets, which possess a periodic electrostatic potential inherent in their structure, In vacancies effectively disrupt this potential field, promote the simultaneous separation and migration of charge carriers, and inhibit their recombination, thereby boosting ROS production and inducing tumor cell pyroptosis via the ROS-NLRP3-caspase-1-GSDMD pathway under ultrasound (US) irradiation. Furthermore, both pristine ZnIn2S4 and ZnIn2S4-VIn nanosheets exhibited remarkable biocompatibility. In vitro and in vivo antineoplastic experiments demonstrate that this sonocatalytic approach effectively promotes tumor elimination, underscoring the critical importance of defect-engineered optimization in sonocatalytic tumor therapy.