Ultrasound-activated nanovesicles for adenosine exhaustion and immune checkpoint blockade in cancer immunotherapy.

Conventional antitumor therapies induce immunogenic cell death (ICD), releasing large amounts of ATP that are rapidly converted into immunosuppressive adenosine within the tumor microenvironment (TME). This accumulation of adenosine promotes tumor immune evasion by inhibiting effector immune cells and upregulating inhibitory immune checkpoints. To overcome this challenge, we designed ultrasound (US)-activated nanovesicle system ADA/Ce6@tLipo which is composed of T cell membranes displaying multiple immune checkpoint molecules and a liposome encapsulating chlorin e6 (Ce6) and adenosine deaminase (ADA). Upon US exposure, these nanovesicles generate reactive oxygen species (ROS) to induce ICD and initiate an antitumor immune response. Concurrently, ADA converts adenosine, produced from ATP breakdown following ICD, into inosine, reversing adenosine-mediated immunosuppression and enhancing T cell activation. Furthermore, the immune checkpoint molecules displayed on the nanovesicles block immune checkpoint ligands on tumor cells, boosting T cell activity and preventing exhaustion. ADA/Ce6@tLipo reprograms the TME by modulating adenosine metabolism and inhibiting multiple immune checkpoints, thereby amplifying T cell-mediated antitumor immunity. This approach offers a promising strategy to enhance the efficacy of cancer immunotherapy.