甲羟戊酸通路是细胞合成脂质、类异戊二烯分子的重要代谢途径，在生物体维持自身基本代谢活动中发挥着至关重要的作用。甲羟戊酸通路的紊乱与人体多种疾病的发生发展有关。该通路有两大类已上市的靶向药物，即他汀类（statins）和双膦酸类（bisphosphonates，BPs）药物。他汀是临床上用来降胆固醇的一线药物，双膦酸则是治疗骨质疏松的首选药物。越来越多的临床研究表明这两类药物能有效降低多种肿瘤的发生率和复发率，但具体作用机制仍不明确。为了揭示甲羟戊酸通路抑制剂与癌症之间的关系，本课题以辛伐他汀和唑来膦酸为工具分子，深入探究了其通过调节免疫系统发挥抗肿瘤作用的机理。首先，我们建立了多种小鼠肿瘤模型，发现甲羟戊酸通路抑制剂经腹腔给药的抗肿瘤作用依赖树突状细胞和T淋巴细胞。其次，通过体外抗原递呈实验和树突状细胞过继回输实验，我们发现甲羟戊酸通路抑制剂能通过促进树突状细胞的抗原交叉递呈能力来发挥抗肿瘤作用。通过比较STING-/-、TRIF-/-、MAVS-/-、IFNAR-/-等敲除小鼠的肿瘤模型，我们证明这种抗原交叉递呈能力的增强依赖STING-I型干扰素信号的活化。进一步的分子生物学实验表明，甲羟戊酸通路抑制剂能延缓STING的降解。根据分子机制研究的结果，我们初步证明甲羟戊酸通路抑制剂能通过阻碍Rab5及Rab7蛋白异戊烯化而限制溶酶体降解STING的能力，间接放大了STING下游的I型干扰素及NF-κB信号。此外，本论文也初步探讨了甲羟戊酸通路抑制剂对肿瘤细胞的作用。综上所述，本工作不仅有助于我们深入理解甲羟戊酸通路与肿瘤免疫信号，尤其是STING-I型干扰素信号的相互作用，也能为靶向甲羟戊酸通路代谢提供新的免疫治疗策略。
The mevalonate pathway is an important metabolic pathway to synthesize lipids and isoprenoids, and plays a crucial role in basic metabolic activities of cells. Disorders of the mevalonate pathway are related to the occurrence and development of various diseases. There are two class of inhibitors targeting this pathway, namely statins and bisphosphonates. Statins are used to lower cholesterol, and bisphosphonates are used for the treatment of osteoporosis. Recent clinical studies have shown that these two drugs can reduce cancer incidence and recurrence, but the underlying mechanisms remain unclear.To reveal the relationship between mevalonate pathway inhibitors (MVAi) and cancer, we used simvastatin and zoledronate as tool molecules to explore their effects on the immune system. First, we established mouse models of various tumors, and found that the antitumor effects of MVAi depended on the dendritic cells and T lymphocytes. Secondly, the results of antigen presentation experiments and dendritic cell adoptive transfer experiments showed that MVAi exerted anti-tumor effects by promoting the cross-priming ability of dendritic cells. Subsequent tumor models of STING-/-, TRIF-/-, MAVS-/-, and IFNAR-/- mice showed that this anti-tumor effects depended on the activation of the STING and IFN-I signaling pathway. Further experiments showed that MVAi could delay STING degradation. Preliminary mechanistic studies revealed that MVAi impeded the prenylation of Rab5 and Rab7 proteins, restrained STING degradation via lysosome, and thereby amplified the downstream IFN-I and NF-κB signaling. Besides, the effects of MVAi on tumor cells were also studied and discussed.In conclusion, this study reveals the interaction between mevalonate pathway and immune response, especially the STING signaling. It will help to discover novel tumor immunotherapy based on mevalonate pathway.
