Multipath ROS Storm and Immune Activation via Sulfur Vacancy-Optimized ZnIn₂S₄ Nanosheets for Piezocatalytic Tumor Therapy

Piezocatalytic therapy is a novel therapeutic strategy that uses mechanical energy to drive catalytic reactions to generate cytotoxic reactive oxygen species (ROS). However, existing materials are limited by low intrinsic catalytic efficiency and a single route to ROS production. This makes it difficult to break through the antioxidant barrier of the tumor microenvironment, which severely limits the antitumor efficacy. Herein, we synthesized sulfur vacancy (S_v)-engineered ZnIn₂S₄ nanosheets (ZIS-2/4/8) by adjusting the concentrations of sulfur source thioacetamide (TAA). The increase in S_v concentration simultaneously achieved the optimization of the energy band structure and the enhancement of the piezoelectric performance (d₃₃ from 21.6 to 46.7 mV V^-1). Under US irradiation, S_v-ZnIn₂S₄ can efficiently generate ROS storms via multiple pathways, including •O₂ ^-, ¹O₂, •OH, and H₂O₂, which overcome the limitations of the tumor microenvironment and achieved effective tumor cell killing. In addition, the ROS storm induced by the ultrasound (US) can also initiate immunogenic cell death (ICD), promoting dendritic cells (DCs) maturation and CD8⁺ T cells infiltration. This multi-pathway ROS burst strategy not only breaks through tumor antioxidant defenses but also induces ICD to form a cascade of immune responses. This demonstrates the advantages of combining piezocatalytic and immunotherapy.