@article{APS11500,
author = {Jin-jin Peng and Min Shao and Yu-yi Li and Jing Feng and Xin-tian Zhang and Che Xu and Qing-xin Xie and Wang-shuang Chen and Jia-qing Chen and Di Wu and Fang Bai and Han Yao and Yu-dao Shen and Xiang-jun Meng},
title = {MS1-96 induces HIP1R-dependent PD-L1 degradation and promotes antitumor immunity in colorectal cancer},
journal = {Acta Pharmacologica Sinica},
volume = {47},
number = {4},
year = {2026},
keywords = {},
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.},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/11500}
}