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

Acta Pharmacologica Sinica volume 47, pages 1015–1028 (2026)Cite this article

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.

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Fig. 1: MS1-96 can decrease PD-L1 levels in CRC cells.
Fig. 2: MS1-96 inhibits PD-1 interaction with CRC cells and enhances T cell-mediated cytotoxicity.
Fig. 3: MS1-96 suppresses CRC xenograft growth by CD8+ T cell-mediated antitumor immunity.
Fig. 4: MS1-96 degrades PD-L1 via lysosome pathway and disturbs PD-L1 N-glycosylation.
Fig. 5: MS1-96 depends on HIP1R to degrade PD-L1.
Fig. 6: MS1-96 enhances the efficacy of PD-1 monoclonal antibody.

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Acknowledgements

This study was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81272745, 81872419, 82102949, and 32071377), the Shanghai Pujiang Talent Program (Grant No. 10PJ1408500), and the Shanghai Frontiers Science Center of Targeted Drugs (Grant No. ZXWH2170101/009).

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  1. These authors contributed equally: Jin-jin Peng, Min Shao, Yu-yi Li

Authors and Affiliations

  1. Department of Gastroenterology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200023, China

    Jin-jin Peng, Yu-yi Li, Jing Feng, Xin-tian Zhang, Che Xu, Qing-xin Xie, Wang-shuang Chen, Jia-qing Chen, Di Wu, Han Yao & Xiang-jun Meng

  2. Shanghai Key Laboratory of Gut Microecology and Associated Major Diseases Research, Shanghai, 200125, China

    Jin-jin Peng, Yu-yi Li, Jing Feng, Xin-tian Zhang, Che Xu, Qing-xin Xie, Wang-shuang Chen, Jia-qing Chen, Di Wu, Han Yao & Xiang-jun Meng

  3. Digestive Disease Research and Clinical Translation Center, Shanghai Jiao Tong University, Shanghai, 200240, China

    Jin-jin Peng, Yu-yi Li, Jing Feng, Xin-tian Zhang, Che Xu, Qing-xin Xie, Wang-shuang Chen, Jia-qing Chen, Di Wu, Han Yao & Xiang-jun Meng

  4. Shanghai Frontiers Science Center of Targeted Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China

    Min Shao & Yu-dao Shen

  5. State Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, 200240, China

    Min Shao & Yu-dao Shen

  6. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China

    Fang Bai

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Contributions

JJP, MS, YYL, HY, YDS and XJM conceived and designed the study. JJP performed animal and cell experiments. MS performed compounds synthesis assays. JJP, YYL, XTZ, JF and CX analyzed the data. JJP, WSC, QXX, WD and JQC prepared figures. JJP, MS, and YYL drafted the manuscript. FB revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Han Yao, Yu-dao Shen or Xiang-jun Meng.

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Peng, Jj., Shao, M., Li, Yy. et al. MS1-96 induces HIP1R-dependent PD-L1 degradation and promotes antitumor immunity in colorectal cancer. Acta Pharmacol Sin 47, 1015–1028 (2026). https://doi.org/10.1038/s41401-025-01681-w

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