Ultrasound-driven defect-engineered piezoelectric heterojunction disrupts the GSH barrier to induce pyroptosis and elicit systemic abscopal antitumor immunity

HB@T nanosheets generate sustained ROS under ultrasound activation, inducing redox collapse and mitochondrial damage. • ROS-mediated mitochondrial injury activates the canonical NLRP3/caspase-1/GSDMD pathway and triggers pyroptotic cell death. • HB@T-induced pyroptosis promotes CRT release, DC maturation, and systemic antitumor immunity with abscopal effects. Triple-negative breast cancer (TNBC) remains one of the most treatment-refractory malignancies, largely attributable to its profoundly immunosuppressive microenvironment that enables tumor immune evasion. Pyroptosis, a gasdermin-mediated lytic cell death pathway, holds promise for reinvigorating antitumor immunity through the release of immunostimulatory signals. However, the clinical translation of pyroptosis-based therapy is hindered by the lack of spatiotemporally controllable triggers and the robust glutathione (GSH)-centered antioxidant defense inherent to TNBC cells. Herein, a defect-engineered core-shell Bi 4 TaO 8 Br@TaO X (HB@T) piezoelectric nanosheet is developed as an ultrasound (US)-responsive platform to circumvent these barriers. Structurally, HB@T comprises a crystalline Bi₄TaO₈Br core that ensures stable charge generation, surrounded by an oxygen-vacancy-rich amorphous Ta-based oxide shell that facilitates oxygen pre-adsorption and GSH consumption. This rational design yields a narrowed bandgap of 2.36 eV and an elevated piezoelectric coefficient (d33 = 24.1 pm V −1 ), enabling efficient electron-hole separation and robust reactive oxygen species (ROS) production under US stimulation. The dual functionality of sustained ROS generation coupled with active GSH depletion synergistically disrupts redox homeostasis in tumor cells, thereby triggering the NLRP3/caspase-1/GSDMD pyroptotic cascade. This process elicits profound immunogenic responses, including dendritic cell maturation, CD8 + T cell infiltration, and expansion of effector memory (T EM ) and central memory (T CM ) T cell populations. Remarkably, in a bilateral tumor model, HB@T treatment achieves 71% inhibition of primary tumors and 67% suppression of distant untreated lesions, demonstrating a potent abscopal effect indicative of systemic immune reactivation. Collectively, this work establishes an innovative therapeutic paradigm that integrates US-activated piezoelectric catalysis with pyroptosis-driven immunomodulation, offering a clinically translatable strategy to overcome immune tolerance in TNBC. Defect-engineered core-shell HB@T piezoelectric nanosheet is developed as an US-responsive platform to induce pyroptosis and elicit systemic abscopal antitumor immunity. The dual functionality of ROS generation coupled with GSH depletion synergistically disrupts redox homeostasis, triggering the NLRP3/caspase-1/GSDMD pyroptotic cascade. Remarkably, HB@T treatment achieves 71% inhibition of primary tumors and 67% suppression of distant untreated lesions, demonstrating a potent abscopal effect indicative of systemic immune reactivation. Download: Download high-res image (128KB) Download: Download full-size image