Overcoming tumor hypoxic bismuth-based ternary heterojunctions enable defect modulation-augmented tumor sonocatalytic immunotherapy

Abstract

Inducing reactive oxygen species (ROS) via sonocatalysis to initiate inflammatory programmed cell death (PANoptosis) and immunogenic cell death (ICD) presents a promising strategy for activatable cancer immunotherapy. However, the limited ROS generation by sonosensitizers under ultrasound and the immunosuppressive tumor microenvironment hinder the efficiency of sono-immunotherapy. To overcome these challenges, a bismuth-based ternary heterojunction, Bi@Bi₂O₃–Pt-PEG (BBOP), was developed for sonocatalytic therapy aimed at activating immune responses. This system enhances ROS production during sonocatalysis and leverages dual therapeutic mechanisms by inducing PANoptosis and ICD to achieve improved anti-tumor efficacy. BBOP forms a Z-scheme heterojunction and Schottky contact through the formation of an intermediate Bi₂O₃ layer and the introduction of Pt. These structures significantly enhance sonocatalytic activity, while the Pt nanozyme exhibits catalase-like behavior, supplying oxygen for sonocatalysis, boosting ROS generation, and effectively relieving tumor hypoxia to reduce immune suppression. Further in vitro and in vivo experiments confirmed BBOP's ability to activate immune responses under ultrasound, inhibiting tumor growth and metastasis. RNA sequencing revealed the therapeutic biological mechanisms. The construction of this catalytic system not only provides insights for optimizing sonosensitizers but also offers a safer and more effective sono-immunotherapy activation strategy and theoretical basis for clinical cancer treatment.