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.
Liu et al. (Fri,) studied this question.