肿瘤免疫治疗是最有可能治愈癌症的方法。目前的肿瘤免疫药物都集中在抗体研究，对小分子肿瘤免疫药物研究相对较少。研究发现TLR1/2成为肿瘤免疫治疗的新靶标，本项目提出将TLR1/2小分子激活剂与PD-L1小分子抑制剂联用，可以激活机体的天然免疫系统，活化细胞毒性T细胞的同时，释放出被肿瘤免疫抑制的T细胞，对肿瘤免疫治疗具有协同效应。申请人以前期筛选1千万个化合物发现的TLR1/2激活剂SMU127为先导物，将分析蛋白识别小分子底物的关键药效特征，结合构效关系及作用机制研究，对其进行更为全面的结构改造，以期获得具有自主知识产权的、高活性、成药性佳的TLR1/2选择性激活剂；并在野生型及TLR2基因敲除小鼠上验证此激活剂的肿瘤免疫效果，以及与PD-L1小分子抑制剂联用后的肿瘤免疫机制，为临床上TLR激活剂（或与PD-1/PD-L1抑制剂联用）抗肿瘤提供理论依据，为肿瘤免疫治疗提供新的选择

Cancer immunotherapy becomes the most potential cure for cancer therapy. The study of immune drugs are focused on antibody research, and few studies are on small molecular drugs. TLR1/2 becomes a new target for small molecule research. This project proposes to combine TLR1/2 agonist with PD-L1 small molecule inhibitors, which can not only activate the body’s immune system, but also inhibit the immune escape of tumors. It can promote antigen-specific humoral and CTL responses and synergize with anti–PD-L1 treatment to inhibit tumor growth. Previously we identified a new TLR1/2 agonist-SMU127. Taking this compound as lead compound, we further carried on the key pharmacodynamic characteristics of protein recognizing small molecular substrates, the structure-activity relationship, and the mechanism research studies to obtain compounds with improved specificity, drug-like property and safety. At the same time, the immunotherapeutic effect and the mechanism of combination of TLR1/2 agonist and PD-L1 small molecule inhibitors will be fully explored on wild and TLR2-/- mice. It also provides a theoretical basis in clinic for the combination of TLR agonists and PD-1/PD-L1 inhibitors and a new choice for cancer immunotherapy.