A tumor microenvironment responsive titanium-based nanosonosensitizer for combination sonodynamic-immunotherapy with calcium ion overload

Ultrasound (US)-triggered sonodynamic therapy (SDT) has become a promising method and has attracted considerable attention for cancer therapy due to its high accuracy, deep tissue penetration, and few side effects. However, the therapeutic efficacy of SDT is limited by the hypoxic tumor microenvironment (TME) and the low quantum yield of sonosensitizers. Immunogenic cell death (ICD) induced by calcium ion overload has attracted widespread attention because it can trigger antitumor immune responses and reconstitute tumor immune microenvironment (TIM). In this study, a TME-responsive CaCO 3 @Pt-TiO 2 nanocomposite (CaPT) was engineered, which combined Pt nanoparticles and CaCO 3 nanoparticles to amplify oxidative stress in cancer cells for cancer sonodynamic immunotherapy. The Pt nanoparticles not only enhanced the reactive oxygen species (ROS) quantum yield of TiO 2 during SDT but also catalyzed the decomposition of H 2 O 2 to overcome tumor hypoxia. The CaCO 3 @Pt-TiO 2 nanocomposite responded to the TME and released a large amount of Ca 2+ , which amplified oxidative stress and triggered robust ICD activation. This process greatly contributed to inflammatory cell infiltration and shifted the TIM from cold to hot. The experimental results confirmed and demonstrated the synergistic therapeutic effects of sonodynamic-immunotherapy in vitro and in vivo . The antitumor mechanisms of sonodynamic immunotherapy were demonstrated by RNA sequencing. This study paves the way for Ti-based nanosensitizers, providing a novel strategy for sonodynamic-assisted immunotherapy.