上海交通大学孟祥军小组的研究显示，MS1-96诱导HIP1R依赖性PD-L1降解并促进结直肠癌的抗肿瘤免疫。这一研究成果于2025年11月3日发表在国际顶尖学术期刊《中国药理学报》上。

在这项研究中，该团队筛选了一个以RKO细胞为主题的同源化合物文库，以发现新的PD-L1下调因子。MS1-96被鉴定为一种有效的PD-L1降解剂，可促进溶酶体依赖性PD-L1降解。

此外，MS1-96可有效降低多种结直肠癌（CRC）细胞系的PD-L1蛋白水平。MS1-96通过破坏PD-1/PD-L1通路，增强CD8⁺ T细胞介导的癌细胞杀伤，并在携带MC38 CRC异种移植物的C57BL/6小鼠中发挥剂量依赖性抗肿瘤作用，口服10天后，肿瘤生长明显受到抑制（100, 200, or 400 mg·kg^-1·d^-1）。机制研究表明，亨廷顿相互作用蛋白1相关（HIP1R）在MS1-96驱动的PD-L1降解中起着不可或缺的作用，HIP1R敲低可消除MS1-96降解PD-L1的能力。MS1-96直接结合PD-L1， K_D为2.58μM和增强HIP1R和PD-L1之间的相互作用，从而改变网格蛋白包被囊泡内PD-L1的细胞内运输。这导致PD-L1转运到再循环核内体的减少，以及转运到后期核内体和溶酶体降解的增加。

此外，MS1-96诱导PD-L1的异常N-糖基化，使蛋白质不稳定并加速其溶酶体介导的降解。

此外，MS1-96有效增强了PD-1抗体在MC38 CRC模型中的抗肿瘤作用。这些发现表明MS1-96为推进肿瘤免疫治疗提供了一种潜在的策略。

据介绍，程序性细胞死亡蛋白1 (PD-1)/程序性死亡配体1 （PD-L1）通路是一个关键的免疫检查点，可使肿瘤免疫逃避，其阻断是癌症免疫治疗的基础。靶向PD-1/PD-L1通路的小分子药物的开发为增强抗肿瘤免疫提供了一种有前景的策略。

附：英文原文

Title: MS1-96 induces HIP1R-dependent PD-L1 degradation and promotes antitumor immunity in colorectal cancer

Author: Peng, Jin-jin, Shao, Min, Li, Yu-yi, Feng, Jing, Zhang, Xin-tian, Xu, Che, Xie, Qing-xin, Chen, Wang-shuang, Chen, Jia-qing, Wu, Di, Bai, Fang, Yao, Han, Shen, Yu-dao, Meng, Xiang-jun

Issue&Volume: 2025-11-03

Abstract: The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway, a pivotal immune checkpoint, enables tumor immune evasion, and its blockade is fundamental to cancer immunotherapy. The development of small-molecule agents targeting the PD-1/PD-L1 pathway offers a promising strategy for enhancing antitumor immunity. In this study, we screened an in-house compound library using RKO cells to discover novel PD-L1 downregulators. MS1-96 was identified as a potent PD-L1 degrader that promotes lysosome-dependent PD-L1 degradation. Furthermore, MS1-96 effectively reduced PD-L1 protein levels across multiple colorectal cancer (CRC) cell lines. By disrupting the PD-1/PD-L1 pathway, MS1-96 enhances CD8+ T cell-mediated killing of carcinoma cells and exerts dose-dependent antitumor effects in C57BL/6 mice bearing MC38 CRC xenografts, resulting in significant tumor growth inhibition after oral administration for 10d (100, 200, or 400mg·kg1·d1). Mechanistic studies revealed that Huntingtin interacting protein 1-related (HIP1R) plays an indispensable role in MS1-96-driven PD-L1 degradation, and HIP1R knockdown abolishes MS1-96’s ability to degrade PD-L1. MS1-96 directly binds to PD-L1 with a KD of 2.58μM and enhances the interaction between HIP1R and PD-L1, thereby altering the intracellular trafficking of PD-L1 within clathrin-coated vesicles. This leads to reduced transport of PD-L1 to recycling endosomes and increased delivery to late endosomes and lysosomes for degradation. Furthermore, MS1-96 induces abnormal N-glycosylation of PD-L1, destabilizing the protein and hastening its lysosome-mediated degradation. Moreover, MS1-96 effectively enhances the antitumor efficacy of PD-1 antibodies in MC38 CRC models. These findings indicate that MS1-96 offers a potential strategy for advancing tumor immunotherapy.

DOI: 10.1038/s41401-025-01681-w

Source: https://www.nature.com/articles/s41401-025-01681-w