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.
Although traditional immunogenic cell death (ICD) inducers generate in situ vaccines (ISV) to potentiate antiprogrammed cell death ligand 1 (anti-PDL1) antibodies therapy, their efficacy remains limited. This limitation may be attributed to the physical barrier created by extracellular matrix (ECM) and immunosuppressive metabolic barrier mediated by adenosine. Here, we report an oncolytic polymer (OP), a well-designed ε-polylysine derivative with ICD-inducing capacity, which can simultaneously facilitate the release of endogenous ECM-degrading enzyme, Cathepsin B. The OP alone is sufficient to induce ISV within tumors and disrupt physical barriers without the need for any additional ECM-regulatory drugs. Furthermore, an oncolytic hydrogel codelivering OP and CD73 inhibitor (AMPCP) was developed (OP@AMPCP Gel). Intratumoral injection of OP@AMPCP Gel generates ISV, decreases tumor ECM deposition, enhances antigen delivery to lymph nodes, increases immune cell infiltration, and promotes penetration of anti-PDL1 antibodies, while reducing adenosine levels. OP@AMPCP Gel+anti-PDL1 treatment showed better therapeutic efficacy than oxaliplatin + anti-PDL1 group against breast cancer. Moreover, 80% of melanoma-bearing mice showed complete tumor regressions after receiving OP@AMPCP Gel + anti-PDL1 treatment. Impressively, OP@AMPCP Gel + anti-PDL1-treated mice showed resistance to tumor rechallenge and metastasis, suggesting induction of long-lasting systemic antitumor immunity. Overall, this study presents an oncolytic hydrogel capable of inducing ISV and remodeling the tumor physical barrier and immunosuppressive barrier, offering a promising strategy for customizing personalized immunotherapy.
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