Ultrasound-responsive release of CD39 inhibitor overcomes adenosine-mediated immunosuppression in triple-negative breast cancer

Triple-negative breast cancer (TNBC), an exceptionally aggressive subtype of breast cancer, is characterized by a poor prognosis and limited treatment options. Although immunotherapy has shown promise for the treatment of TNBC, the immunosuppressive accumulation of adenosine (ADO) in the tumor microenvironment (TME) contributes to immune evasion and tumor progression. To address this challenge, we introduce a novel ultrasound-responsive liposomal system (BFPL) designed to inhibit ADO production and enhance the effectiveness of sonoimmunotherapy. BFPL consists of lipid membranes loaded with an endoplasmic reticulum (ER)-targeting sonosensitizer (PMPS) and a reactive oxygen species (ROS)-responsive CD39 inhibitor (FPL-67156) polyplex, synthesized via the thin-film hydration method. Upon ultrasound irradiation, BFPL generates substantial ROS, inducing robust immunogenic cell death (ICD) through ER stress. Concurrently, ROS-mediated deboronation of the polyplex releases FPL-67156, which inhibits ATP degradation into ADO, thereby promoting dendritic cell maturation and activating effector T cells. Moreover, BFPL effectively triggers a potent antitumor immune response and enhances the efficacy of anti–PD-L1 immunotherapy. Thus, by modulating metabolic pathways to counteract ADO-associated barriers in ICD therapy, this innovative approach holds potential for improving immunotherapy outcomes in TNBC.