HIFU postoperative hypoxia enables metal-organic frameworks amplifying banoxantrone and STING activation for enhanced immunotherapy

High-intensity focused ultrasound (HIFU) represents a game-changing breast-conserving treatment, with its induced immune response playing a crucial role in prognosis. However, the low immunogenicity and immunosuppressive microenvironment of tumors after surgery have prevented HIFU from generating strong antitumor immune responses, resulting in tumor recurrence and metastasis. Herein, we developed CaCO 3 -loaded metal–organic frameworks (MOFs) comprising Mn 2+ , hypoxia-activated prodrug banoxantrone (AQ4N), and stimulator of interferon genes (STING) agonist SR-717 to enhance HIFU-induced antitumor immunotherapy. Upon effective accumulation and drug release within tumor microenvironment (TME), MOFs exploit HIFU-exacerbated hypoxia to activate AQ4N, thereby inducing immunogenic cell death and enhancing tumor immunogenicity. Meanwhile, Mn 2+ enhances the activity of SR-717, synergistically amplifying STING activation and effectively promoting immune cell infiltration. Moreover, CaCO 3 complements immunotherapy by depleting lactate in TME, remodeling the immune microenvironment. As a result, MOFs enhance HIFU postoperative antitumor immune responses, significantly inhibiting tumor recurrence and metastasis. This work provides valuable insights to improve the prognosis of all surgical procedures, including HIFU.