Ultrasound‐Responsive Bimetallic Hydroxide for Inducing Pyroptosis and Reversal of Immunosuppressive Microenvironment

ABSTRACT The efficacy of immunotherapy for triple‐negative breast cancer (TNBC) is limited by low tumor immunogenicity and the highly immunosuppressive tumor microenvironment (TME). Herein, a multifunctional cobalt‐doped layered hydroxide nanoplate (Co‐LDH) is developed via a simple one‐step method, which acts as a novel sonosensitizer and β‐catenin inhibitor to enhance anti‐tumor immune response. The synthesized Co‐LDH is endowed with simultaneous glutathione (GSH) depletion and reactive oxygen species (ROS) generation in tumor cells, due to the existence of Co 2+ /Co 3+ redox couple. Moreover, Co‐LDH is found to be sensitive to exogenous ultrasound (US) stimulation, possessing strong capability of ROS bursts in sonodynamic therapy (SDT), which, together with GSH consumption, induces significant pyroptosis of tumor cells and releases damage‐associated molecular patterns (DAMPs), thereby elevating immunogenicity. More importantly, we first find that Co‐LDH can remodel the immunosuppressive TME by reducing tumor acidity and downregulating the β‐catenin/programmed death‐ligand 1 (PD‐L1) pathway to suppress invasion and reverse immune evasion. In bilateral tumor models, Co‐LDH can efficiently suppress primary and distant tumor growth and enhance the infiltration of T cells in tumor tissues. Overall, this multifunctional cobalt‐doped LDH nanomedicine is endowed with simultaneous enhancement of immunogenicity and reversal of immunosuppressive TME, offering a valuable reference in effective tumor therapy.