Metal‐Organic Framework‐Mediated Synergistic Hypoxia‐Activated Chemo‐Immunotherapy Induced by High Intensity Focused Ultrasound for Enhanced Cancer Theranostics

High intensity focused ultrasound (HIFU) has attracted considerable attention as a noninvasive, efficient, and economic therapeutic modality for solid tumors. However, HIFU surgery has its intrinsic limitation in completely ablating tumors, leading to residual tumor tissue. Furthermore, the severely hypoxic environment ensuring after surgery can exacerbate the unrestricted proliferation and metabolism of residual tumor cells, leading to tumor recurrence and metastasis. To address these limitations, a versatile HIFU‐specific metal‐organic framework nanosystem (called ADMOFs) is developed by coordinating hypoxia‐activated prodrug AQ4N, Mn2+, and DOX based on the postoperative response to changes in the tumor microenvironment. ADMOFs loaded with AQ4N/Mn2+ exhibited remarkable tumor‐targeting behavior in vivo and enhanced photoacoustic/magnetic resonance imaging effects, enabling more accurate guidance for HIFU surgery. After surgery, the ADMOFs exploited the severely hypoxic tumor environment induced by HIFU, overcoming hypoxia‐associated drug resistance, and inducing immunogenic cell death. Finally, it effectively inhibited tumor growth and eliminated lung metastasis. Transcriptome studies revealed that this strategy significantly up‐regulated genes involved in apoptosis, cell cycle, and HIF‐1 signaling pathway while downregulating genes related to tumor proliferation and metastasis. These findings suggest that combining hypoxia‐activated chemo‐immunotherapy with HIFU is a promising strategy for enhancing cancer theranostics. The HIFU‐specific metal‐organic framework nanosystem (ADMOFs) is constructed by coordinating AQ4N, Mn2+, and DOX. ADMOFs can efficiently enhance PA/MR imaging to more accurately guide HIFU surgery. Moreover, ADMOFs utilize the severe tumor hypoxic environment created by HIFU to conquer hypoxia‐associated drug resistance and kill residual hypoxic/normoxic tumor cells. This strategy innovatively combines hypoxic‐activated chemotherapy with HIFU to enhance cancer treatment.