A novel adenosine 2A receptor antagonist HZ-086 enhances the efficiency of immunotherapy and alleviates the acquired resistance to PD-L1 by restoration of T cell functions

Abstract

Immunotherapy faces significant challenges due to low clinical response rates and immune escape mechanisms, which ultimately lead to drug resistance. Previous studies suggest that adenosine-2A receptor (A_2AR) signaling plays a critical role in immunosuppression and immune escape. However, no potent and selective A_2AR inhibitors are currently available for clinical use to address immunotherapy resistance in tumors. In this study, we identified a novel small molecule compound, HZ-086, as a potent and selective inhibitor of A_2AR. HZ-086 restored the activation of T-cell signaling which is suppressed by adenosine analogs in vitro. Additionally, HZ-086 enhanced T-cell-mediated cytotoxicity, increased the secretion of cytokines for antitumor and subsequently inhibited growth of tumor cells in vitro and in vivo. Furthermore, HZ-086 inhibited tumor growth, enhances anti-tumor capacity, and reversed PD-L1 resistance in vivo. When combined with FD-L1, a PD-L1 small molecule inhibitor discovered by our lab, HZ-086 achieved over 80 % tumor growth inhibition (TGI) and restored immune response in anti-PD-L1 monoclonal antibody-resistant tumors. This combination treatment also promoted the infiltration and activation of CD8⁺ T lymphocytes within the tumor microenvironment. Our findings demonstrate that adenosine-A_2AR signaling mediates resistance to immunotherapy and discover a novel potent and selective A_2AR inhibitor with high efficacy in enhancing antitumor immune responses and reversing PD-L1 resistance. The combination of A_2AR inhibitor and PD-L1 inhibitor represents a promising therapeutic strategy for antitumor therapy.