皮肤黑素瘤恶性程度极高，虽然免疫检查点阻断剂（ICBs）对其临床疗效良好，但总体响应率小于40%。因此从现有临床药物中筛选辅药与ICBs结合提高免疫治疗效果是目前基础研究与临床试验中的重要方向。本研究发现抗寄生虫药Albendazole（ABZ）能增强小鼠免疫活性、抑制黑素瘤生长。机制研究表明ABZ通过蛋白水平而非转录水平下调PD-L1，促进PD-L1泛素化降解。通过IP-MS发现泛素化调控蛋白UBQLN4与PD-L1互作，且敲低UBQLN4能下调PD-L1，ABZ又能下调UBQLN4。综上，本项目提出以下科学假说：UBQLN4能与PD-L1互作并稳定其表达，ABZ通过下调UBQLN4引起PD-L1泛素化降解，增强T细胞活性进而增强肿瘤免疫、抑制黑素瘤生长。本项目首次阐明ABZ增强肿瘤免疫的作用与机制，并为基于anti-CTLA-4的联合免疫治疗提供一个现有参考药物，具有重要临床转化意义。

Melanoma is an extremely malignant skin tumor, although immune checkpoint blockers (ICBs) have shown good clinical efficacy on this disease, however, the overall response rate is less than 40%. Therefore, it is an important undertaking in basic research and clinical trials to screen the existing clinical drugs with good curative activity and fewer side effects to combine with ICBs to improve the effectiveness of cancer immunotherapy against melanoma. In this study, we found that Albendazole (ABZ), a conventional anthelmintic medication, enhances the immune activity of mice and inhibits melanoma cell growth. Studies on molecular mechanism revealed that ABZ down-regulates PD-L1 at the protein level rather than at the transcription level, and promotes ubiquitin-degradation of PD-L1. Using IP-MS we found that the ubiquitination regulatory protein, UBQLN4, interacts with PD-L1. Furthermore, we observed that knockdown of UBQLN4 down-regulated PD-L1, while treatment with ABZ down-regulated UBQLN4. Taken together, this project proposes the following scientific hypothesis: UBQLN4 can interact with PD-L1 and stabilize the protein level of PD-L1, and ABZ down-regulates UBQLN4 to induce ubiquitin-degradation of PD-L1, thereby enhances the activity of CD8+ T cells, that increases anti-tumor immunity further to inhibit the growth of melanoma. This project, for the first time, is aimed to clarify the role and molecular mechanism of ABZ in enhancing anti-tumor immunity and to provide an existing clinical drug for anti-CTLA-4-based combined immunotherapy for melanoma. Successful completion of this project would be of great significance for the transformation of basic research into clinical application.