Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers. Indoleamine 2,3-dioxygenase 1 (IDO1), an immune checkpoint, plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy. Proteolysis Targeting Chimeras (PROTAC) technology has emerged as a new model for drug research and development for its advantageous mechanism. Herein, we reported the application of PROTAC technology in targeted degradation of IDO1, leading to the discovery of the first IDO1 PROTAC degrader 2c, which induced significant and persistent degradation of IDO1 with maximum degradation (d_max) of 93% in HeLa cells. Western-blot based mechanistic studies indicated that IDO1 was degraded by 2c through the ubiquitin proteasome system (UPS). Label-free real-time cell analysis (RTCA) indicated that 2c moderately improved tumor-killing activity of chimeric antigen receptor-modified T (CAR-T) cells. Collectively, these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.

癌症免疫疗法正在彻底改变肿瘤学，并已成为治疗多种癌症的一种有前途的策略。吲哚胺2,3-二加氧酶1（IDO1）是一种免疫检查点，通过调节多种免疫细胞在肿瘤免疫逃逸中发挥重要作用，并已被认为是癌症免疫疗法的诱人靶标。靶向靶向嵌合体蛋白水解（PROTAC）技术因其优越的机理而成为药物研发的新模型。在此，我们报道了PROTAC技术在IDO1的靶向降解中的应用，从而导致发现了第一个IDO1 PROTAC降解剂2c，该降解剂诱导了IDO1的持续显着降解，并具有最大降解量（d _max）在HeLa细胞中占93％。基于蛋白质印迹的机理研究表明，IDO1通过泛素蛋白酶体系统（UPS）被2c降解。无标记实时细胞分析（RTCA）表明2c适度提高了嵌合抗原受体修饰的T（CAR-T）细胞的杀肿瘤活性。总体而言，这些数据为PROTAC技术在肿瘤免疫相关蛋白中的应用提供了新的见识，也是研究IDO1功能的有前途的工具。