近年来，随着免疫检查点抑制剂与CAR-T等细胞免疫治疗的崛起，肿瘤免疫治疗在部分肿瘤中取得了显著的疗效。但现有免疫治疗的总体反应率不高，主要原因是肿瘤具有复杂的免疫抑制机制。因此，发现并靶向新的肿瘤免疫抑制通路，对提高免疫治疗的效果至关重要。CNR2是免疫系统特异的大麻素受体，其激动剂抑制免疫反应，被广泛用于抗炎和肿瘤辅助治疗。但其在肿瘤免疫中的作用尚无研究，激动剂药物也可能抑制肿瘤免疫反应而加速肿瘤进展。我们前期研究发现CNR2在肿瘤浸润T细胞中高表达，并且敲除CNR2显著延缓小鼠肿瘤生长，表明CNR2参与肿瘤免疫抑制。本项目将研究CNR2在T细胞耗竭中的作用与机制；明确CNR2激动剂药物是否促进肿瘤生长；同时通过阻断CNR2建立免疫治疗新方法，并与现有免疫治疗药物联合，建立更好的治疗方案。研究结果将阐明新的肿瘤免疫抑制机制，并为临床开展阻断CNR2的肿瘤免疫治疗提供理论基础。

Recently, arising with the prevalent and comprehensive application of checkpoint inhibitor and CAR-T in clinical cancer treatment, the idea of tumor immunotherapy has developed in an unprecedented way. While due to existence of complicated tumor derived immunosuppression mechanisms, immunotherapy always ends with limited clinical outcomes, so focusing on tumor immunosuppressive pathway is the matter of the fact to improve the outcome of immunotherapy. CNR2 is an immuno-specific cannabinoid receptor, and its agonists are immunosuppressive and widely used in anti-inflammation and anti-tumor treatment, but its role in tumor immunity has not been studied yet. Those drugs may promote tumor progression via inhibiting immune function according to our former data, CNR2 in tumor infiltrating lymphocytes are highly expressed and delayed tumor progression is observed in CNR2 knockout mice which means CNR2 are related with tumor immunosuppression. In this study, we will focus on function and potential mechanisms of CNR2 induced T cell exhaustion, clarify whether the usage of CNR2 agonists would aid tumor growth, establish new therapeutic targets for immunotherapy, improved new tumor therapeutic scheme would be established in the future which combined with existed treatments. The results will provide theoretical basis of immunosuppression and may further clarify the availability for the new therapeutic method by targeting CNR2.