Advances in Stimuli-Responsive Release Strategies for Sonosensitizers in Synergistic Sonodynamic Immunotherapy against Tumors.

Abstract

Despite intensive efforts to develop diagnostic and therapeutic tools, the successful treatment of cancer is still hampered by uncontrolled tumor proliferation and metastasis. Sonodynamic therapy (SDT) is a cutting-edge, noninvasive treatment modality that activates sonosensitizers via low-intensity ultrasound (US) to generate reactive oxygen species (ROS), offering deep tissue penetration, low phototoxicity, and minimal side effects. Beyond direct cytotoxicity, it can trigger immunogenic cell death (ICD), thereby enhancing systemic antitumor immune responses. However, its efficacy is constrained by the immunosuppressive tumor microenvironment (ITME). To address these limitations, growing research efforts have focused on dual therapeutic strategies that combine SDT with tumor immunotherapy. These strategies are designed to enhance tumor-specific accumulation of sonosensitizers through stimuli-responsive release mechanisms. SDT activates immune pathways and induces ICD, thus remodeling the tumor microenvironment (TME) and converting immunologically "cold" tumors into "hot" tumors. This transformation effectively addresses the low response rates and immune-related adverse events associated with immunotherapy, while enhancing immune recognition and tumor clearance. This review summarizes recent advances in the development of stimuli-responsive release strategies for sonosensitizers in sonodynamic immunotherapy, discusses the challenges hindering clinical translation, and underscores the potential of this dual therapeutic strategy in advancing cancer treatment.