A Self‐Immunoregulatory Nanosensitizer for Sonodynamic Cancer Therapy

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.