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A Self-Immunoregulatory Nanosensitizer for Sonodynamic Cancer Therapy
Jiahao Liu1,2, Zaigang Zhou2, Cheng Li1
1Department of Urology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Abstract:
Sonodynamic therapy (SDT) generates reactive oxygen species (ROS) for noninvasive, spatiotemporally controlled tumor therapy. However, whether ROS-driven stress also reprograms tumor immune signaling toward immune resistance, thereby limiting durable antitumor immunity, remains unclear. This study reveals that immune resistance is a universal mechanism shared by three major classes of clinically used SDT sensitizers. A porphyrin-biguanide-loaded albumin nanoparticle (POR-BG@Alb) is rationally developed as a self-immunoregulatory sonosensitizer, which induces mitochondrial dysfunction to activate AMP-activated protein kinase (AMPK) and suppress c-MYC, concomitantly downregulating PD-L1 and CD47 and enhancing T-cell killing and macrophage phagocytosis. Unlike clinically used traditional sensitizers that upregulate PD-L1/CD47 after SDT and promote innate and adaptive immunosuppression, POR-BG@Alb amplifies sonodynamic efficacy while limiting this feedback. Across orthotopic bladder cancer, subcutaneous xenograft, and orthotopic breast cancer models, POR-BG@Alb-mediated SDT suppresses primary tumors, elicits abscopal antimetastatic effects, establishes immune memory, and extends median survival in subcutaneous xenografts from 17 to 44 days. Collectively, this research unmasks a previously unappreciated role of SDT in inducing immune resistance and shows that POR-BG@Alb integrates potent sonodynamic activity with self-oxygen regulation and self-immunoregulation to enable durable systemic antitumor immunity, providing a promising nanotherapeutic strategy for SDT clinical translation.
Insights
Sonodynamic therapy (SDT) can cause immune resistance. A new nanoparticle (POR-BG@Alb) enhances SDT efficacy and promotes lasting antitumor immunity by regulating immune signaling.
Area of Science:
- Oncology
- Nanomedicine
- Immunotherapy
Background:
- Sonodynamic therapy (SDT) utilizes reactive oxygen species (ROS) for targeted tumor treatment.
- The impact of ROS-driven stress on tumor immune signaling and resistance remains largely unknown.
- Existing SDT sensitizers may inadvertently promote immune suppression, limiting durable antitumor responses.
Purpose of the Study:
- To investigate the potential of SDT to induce immune resistance.
- To develop a novel self-immunoregulatory sonosensitizer to overcome SDT-induced immune suppression.
- To evaluate the therapeutic efficacy and immunomodulatory effects of the novel sonosensitizer.
Main Methods:
- Development of porphyrin-biguanide-loaded albumin nanoparticles (POR-BG@Alb).
- Assessment of POR-BG@Alb-mediated SDT effects on tumor cells and immune cells in vitro and in vivo.
- Evaluation of tumor growth, metastasis, immune memory, and survival in preclinical cancer models.
Main Results:
- Three major classes of clinical SDT sensitizers were found to universally induce immune resistance.
- POR-BG@Alb-mediated SDT activated AMPK, suppressed c-MYC, and downregulated immune checkpoint proteins PD-L1 and CD47.
- This approach enhanced T-cell killing and macrophage phagocytosis, suppressed primary tumors, induced abscopal antimetastatic effects, and established immune memory, significantly extending survival.
Conclusions:
- SDT can paradoxically induce immune resistance, hindering durable antitumor immunity.
- POR-BG@Alb represents a promising nanotherapeutic strategy that integrates potent sonodynamic activity with self-immunoregulation.
- This novel approach overcomes SDT-induced immune suppression, enabling durable systemic antitumor immunity for improved clinical translation.
