Tumor Eradication via UTMC-Induced Thrombotic Infarction Combined with Redox-Responsive Nanoparticle-Mediated Chemo-Immunotherapy

Tumor infarction is a promising treatment strategy that delivers benefits such as short therapeutic duration, low resistance potential, and broad applicability across diverse tumor types. However, treatments that induce vascular thrombosis cannot secure durable tumor elimination due to relapse caused by residual tumor cells (often localized in the surviving rim). To address this limitation, we combined tumor infarction therapy with chemotherapy and immunotherapy. Nonfocused ultrasound-targeted microbubble cavitation (UTMC) was used to induce vascular infarction by generating homogeneous and durable thrombosis while minimizing off-target damage. Simultaneously, redox-responsive liposomal camptothecin (CPT)-MSA-2 nanoparticles (CM NPs) were synthesized by coassembling sphingomyelin-derived CPT and the stimulator of interferon genes agonist MSA-2, which facilitates tumor-specific drug release in reductive microenvironments. Critically, CM NPs eradicated residual tumor cells that evaded infarction, thereby preventing recurrence. In murine tumor models, combining UTMC and CM NPs significantly enhanced therapeutic accumulation in tumors by 1.8-fold, suppressed primary tumor growth, eliminated recurrence, reduced lung metastasis by 71%, and extended median survival to 60 days, surpassing the therapeutic performance of all monotherapies. This multimodal strategy concurrently targets tumor vasculature, residual cells, and immunosuppression, thereby overcoming the limitations of conventional infarction therapy.