Hypoxia-responsive albumin nanoparticles co-delivering banoxantrone and STING agonist enhance immunotherapy of high-intensity focused ultrasound

High-intensity focused ultrasound (HIFU) has great potential as a noninvasive, breast-conserving treatment for patients with breast cancer. The HIFU-induced antitumor immune response plays a critical role in postoperative prognosis. However, after surgery, tumor cells exhibit low immunogenicity, and severe hypoxia exacerbates the immunosuppressive tumor microenvironment, thereby rendering HIFU-induced immune effects insufficient to prevent tumor recurrence and metastasis. Herein, hypoxia-responsive, crosslinked albumin-based nanoparticles (HACS NPs), comprising the hypoxia-activated prodrug AQ4N, the stimulator of interferon genes (STING) agonist SR-717, and calcium carbonate (CaCO 3 ), were developed to augment the postoperative antitumor immune response. The HACS NPs are activated to “on” state in the postoperative hypoxic tumor microenvironment and release the loaded AQ4N to increase immunogenic cell death (ICD). Moreover, SR-717 promotes intratumoral infiltration of immune cells through STING activation, while CaCO 3 creates immune-supportive tumor microenvironment by consuming lactate, thereby polarizing M2 macrophages to the M1 phenotype. Based on these improvements, the HACS NPs have been shown to significantly enhance the post-HIFU antitumor immune response, effectively suppress tumor recurrence and metastasis. This work provides a successful paradigm for improving the prognosis of surgical interventions, including HIFU.