A controllable self-amplifying oxidative stress strategy for boosting noninvasive sonodynamic therapy and synergistic immunotherapy.

The combined application of sonodynamic therapy (SDT) and immune checkpoint blockade may be hindered by the antioxidant defense mechanisms of tumor cells and the immunosuppressive tumor microenvironment (TME). SDT may be enhanced through nanotechnology to improve sonosensitizer delivery and drug release triggered by reactive oxygen species (ROS). However, strategies to amplify ROS cascades and synergize with immune checkpoint blockade remain underexplored. In this study, a pH/ROS dual-responsive nanoplatform (designated as FHPCL NPs) that targets tumor tissues with a "self-amplifying oxidative stress" strategy to synergistically enhance the efficacy of SDT and immunotherapy was developed. This nanoplatform established a "drug release-ROS generation-carrier disintegration" positive feedback loop in the tumor tissues when combined with ultrasound technology, thereby inducing massive ROS production. In a 4T1 breast cancer model, this strategy achieved an in situ tumor suppression rate exceeding 80 %. Importantly, the integrated platform significantly promotes dendritic cell maturation and cytotoxic T lymphocytes infiltration by inducing immunogenic cell death, thereby activating enhanced immune responses and systemic immunological effects. Furthermore, we demonstrated that combining FHPCL NPs-augmented SDT with anti-programmed death ligand 1 markedly inhibited tumor growth and pulmonary metastasis, and established durable immune memory. This study provides a promising strategy for tumor therapy.