Ultrasound-Activatable Nanoprobes for Imaging-Guided Inhibition of Immunosuppressor Production in Tumor Microenvironment

The immunosuppressive tumor microenvironment (TME), characterized by elevated adenosine levels, poses a significant barrier to effective cancer immunotherapy. Herein, we report an ultrasound-activatable nanoprobe based on piezoelectric quantum dots (QDs) emitting in the near-infrared-IIb (NIR-IIb) window. The nanoprobe integrates a fluorescent QDs core with tumor-targeting peptides and CD73 inhibitors conjugated via a reactive oxygen species (ROS)-responsive linker. Attributed to the optimized piezoelectricity of the QDs core, this nanoprobe could generate ROS under deep-penetrating ultrasound irradiation. The bright NIR-IIb fluorescence and tumor-targeting ability enable the noninvasive delineation of the tumor margin from normal tissue, guiding the optimal scope and timing of ultrasound treatment. The precise ultrasound irradiation triggers the cleavage of the ROS-responsive linker and the release of the CD73 inhibitor, which effectively inhibits the production of adenosine in TME. This reduction alleviates immunosuppression and robustly activates antitumor immunity in mice, achieving significant therapeutic efficacy. This work provides a promising strategy for overcoming adenosine-mediated immunosuppression and advancing precise ultrasound therapy for cancers.