Stimuli-responsive nanoplatforms for sonodynamic immunotherapy: opportunities and challenges in cancer treatment

Stimulus-responsive sonodynamic immunotherapy is a promising non-invasive strategy that combines ultrasound-activated Sonodynamic therapy (SDT) with a smart stimulus-responsive nanodelivery system to overcome the limitations of traditional cancer therapies. By utilizing signals from the tumor microenvironment (TME), such as acidic pH, high glutathione (GSH) levels, enzyme overexpression, and hypoxia, stimulus-responsive nanosonic sensitizers enable precise, on-demand release and deep tumor penetration. Ultrasound activation generates reactive oxygen species (ROS) and cavitation effects, inducing immunogenic cell death (ICD), characterized by damage-associated molecular patterns (DAMPs) and exposure/release of tumor-associated antigens (TAAs). This approach can transform "cold" tumors into "hot" tumors, promoting dendritic cell maturation, cytotoxic T lymphocyte (CTL) infiltration, and systemic antitumor immunity, including remote effects and long-term immune memory. When combined with immune checkpoint blockade (ICB), chemodynamic therapy (CDT), gas therapy, photothermal (PTT)/photodynamic therapy (PDT), or gene therapy, stimulus-responsive sonodynamic immunotherapy can significantly improve tumor suppression rates, reduce metastasis, and minimize systemic toxicity. Despite significant progress in preclinical studies, clinical translation still faces numerous challenges, including low ICD efficiency in hypoxic tumors, TME heterogeneity, parameter standardization, and optimization of the dual role of High migration group box 1 (HMGB1). This review summarizes the mechanisms, stimulus-response strategies, multimodal synergistic effects, and current clinical progress of stimulus-responsive sonodynamic immunotherapy, highlighting its opportunities and key challenges in future precision cancer treatment.