2. Academic Validation
  3. MS1-96 induces HIP1R-dependent PD-L1 degradation and promotes antitumor immunity in colorectal cancer

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

  • Acta Pharmacol Sin. 2025 Nov 3. doi: 10.1038/s41401-025-01681-w.
Jin-Jin Peng # 1 2 3,  Min Shao # 4 5,  Yu-Yi Li # 1 2 3,  Jing Feng 1 2 3,  Xin-Tian Zhang 1 2 3,  Che Xu 1 2 3,  Qing-Xin Xie 1 2 3,  Wang-Shuang Chen 1 2 3,  Jia-Qing Chen 1 2 3,  Di Wu 1 2 3,  Fang Bai 6,  Han Yao 7 8 9,  Yu-Dao Shen 10 11,  Xiang-Jun Meng 12 13 14
Affiliations

Affiliations

  • 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.
  • 7 Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200023, China. hanyao89@163.com.
  • 8 Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, 200125, China. hanyao89@163.com.
  • 9 Digestive Disease Research and Clinical Translation Center, Shanghai Jiao Tong University, Shanghai, 200240, China. hanyao89@163.com.
  • 10 Shanghai Frontiers Science Center of Targeted Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. yudao.shen@sjtu.edu.cn.
  • 11 State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China. yudao.shen@sjtu.edu.cn.
  • 12 Department of Gastroenterology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200023, China. xiangjunmeng@aliyun.com.
  • 13 Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, 200125, China. xiangjunmeng@aliyun.com.
  • 14 Digestive Disease Research and Clinical Translation Center, Shanghai Jiao Tong University, Shanghai, 200240, China. xiangjunmeng@aliyun.com.
  • # Contributed equally.
PMID: 41184620 DOI: 10.1038/s41401-025-01681-w
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

HIP1R; MS1-96; PD-L1; antitumor immunity; colorectal cancer; lysosomal degradation.

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