A Redox-Responsive Nanovaccine Combined with A2A Receptor Antagonist for Cancer Immunotherapy

In situ vaccination can trigger an antitumor immune response. However, the therapeutic effect is still limited since the high expression of adenosine binding to G protein-coupled receptor A2AR induces an immunosuppressive effect. In this work, a new formulation is presented with the combination of a nanovaccine based on redox-responsive polymer micelles and A2AR antagonist SCH58261. The micelles simultaneously encapsulate immunogenic cell death (ICD) inducer doxorubicin (DOX) and adjuvant Toll-like Receptor 7 and 8 (TLR7/8) agonist R848, acting as the potent in situ vaccines. A high concentration of glutathione in tumor cells leads to the disintegration of these micelles, releasing DOX and R848 to mediate ICD, inducing the activation of dendritic cells and initiating an immune response. Meanwhile, A2AR antagonist SCH58261, a generation immune checkpoint blocker, inhibits the immunosuppressive adenosinergic pathway in the tumor microenvironment, activating natural killer (NK) cells and CD8⁺ T cells, and inhibiting the proliferation of regulatory T cells. Therefore, this formulation can trigger a robust systemic antitumor immune response.