Stimulus-responsive sonodynamic immunotherapy shows promise in preclinical cancer models

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Frontiers in Medicine Published May 29, 2026 Medically reviewed May 29, 2026 DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Interpret this preclinical review as early-stage; sonodynamic immunotherapy faces hypoxia and heterogeneity hurdles.

This narrative review discusses the emerging field of stimulus-responsive sonodynamic immunotherapy for cancer. The approach combines ultrasound-activated sonodynamic therapy (SDT) with a smart stimulus-responsive nanodelivery system to enhance immune responses. The review synthesizes preclinical evidence on the mechanisms and potential of this strategy, highlighting its ability to induce immunogenic cell death (ICD) and modulate the tumor microenvironment (TME).

Key findings from preclinical studies suggest that this combination can improve the efficacy of SDT by enabling targeted drug release and overcoming some limitations of conventional SDT. However, the authors note several significant limitations. Low ICD efficiency in hypoxic tumors remains a major hurdle, as hypoxia reduces the effectiveness of SDT. Additionally, TME heterogeneity complicates treatment response, and parameter standardization is lacking across studies. The dual role of High mobility group box 1 (HMGB1) in cancer progression also requires careful optimization.

Overall, while the concept is promising, the evidence is entirely preclinical, and no clinical data are available. The review does not report on safety, efficacy, or practice relevance. Clinicians should interpret these findings as early-stage research that requires substantial further investigation before any clinical application.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

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.