HIFU postoperative hypoxia-activated metal-organic frameworks modulate the tumor microenvironment to augment immunotherapy

Limited intensity and duration of high-intensity focused ultrasound (HIFU)-induced immune response largely hinder postoperative immunotherapy due to low immunogenicity and immunosuppression of tumor microenvironment (TME). In this study, effect-specific metal-organic frameworks (MOFs) were designed based on the severe hypoxia of postoperative tumors through regulating TME to enhance body's antitumor immune response. The combination of iron ions, hypoxic-activated prodrug banoxantrone, and indoleamine 2,3-dioxygenase (IDO) signaling pathway inhibitor NLG919 is utilized to construct MOFs loaded with CaCO₃, which achieves intraoperative monitoring via photoacoustic imaging for precise ablation of tumors. Ingeniously, banoxantrone, within the severely hypoxic environment of tumors induced by HIFU, is activated in the manner of converting enemies into friends and cooperates with iron ions to effectively trigger immunogenic cell death (ICD) in tumors. In addition, the immunosuppressive microenvironment exacerbated by postoperative hypoxia is degraded via the cooperation of NLG919, which blocks the IDO-1 signaling pathway and CaCO₃, which consumes lactic acid. Based on these improvements, well-designed MOFs effectively inhibit bilateral tumor growth/metastasis and offer a successful paradigm for improving the overall prognosis of HIFU.