Article

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

Jin-jin Peng1,2,3, Min Shao4,5, Yu-yi Li1,2,3, Jing Feng1,2,3, Xin-tian Zhang1,2,3, Che Xu1,2,3, Qing-xin Xie1,2,3, Wang-shuang Chen1,2,3, Jia-qing Chen1,2,3, Di Wu1,2,3, Fang Bai6, Han Yao1,2,3, Yu-dao Shen4,5, Xiang-jun Meng1,2,3
1 Department of Gastroenterology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200023, China
2 Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai 200125, China
3 Digestive Disease Research and Clinical Translation Center, Shanghai Jiao Tong University, Shanghai 200240, China
4 Shanghai Frontiers Science Center of Targeted Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China
5 State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China
6 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
Correspondence to: Han Yao: hanyao89@163.com, Yu-dao Shen: yudao.shen@sjtu.edu.cn, Xiang-jun Meng: xiangjunmeng@aliyun.com,
DOI: 10.1038/s41401-025-01681-w
Received: 21 April 2025
Accepted: 21 September 2025
Advance online: 3 November 2025

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 10 d (100, 200, or 400 mg·kg-1·d-1). 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 2.58 μM 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.
Keywords: colorectal cancer; antitumor immunity; PD-L1; MS1-96; lysosomal degradation; HIP1R

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