Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment
Chengliang Sun, Mingxiao Yin, Yao Cheng, Zean Kuang, Xiaojia Liu, Gefei Wang, Xiao Wang, Kai Yuan, Wenjian Min, Jingwen Dong, Yi Hou, Lingrong Hu, Guoyu Zhang, Wenli Pei, Liping Wang, Yanze Sun, Xinmiao Yu, Yibei Xiao, Hongbin Deng, Peng Yang
Abstract
Blocking the PD-1/PD-L1 interaction has become an important strategy for tumor therapy, which has shown outstanding therapeutic effects in clinical settings. However, unsatisfactory response rates and immune-related adverse effects limit the use of anti-PD1/PD-L1 antibodies. Here, we report the discovery and identification of S4-1, an innovative small-molecule inhibitor of PD-L1. In vitro, S4-1 effectively altered the PD-L1/PD-1 interaction, induced PD-L1 dimerization and internalization, improved its localization to endoplasmic reticulum, and thus enhanced the cytotoxicity of peripheral blood mononuclear cells toward tumor cells. In vivo, S4-1 significantly inhibited tumor growth in both lung and colorectal cancer models, particularly in colorectal cancer, where it led to complete clearance of a portion of the tumor cells. Furthermore, S4-1 induced T-cell activation and inversed the inhibitory tumor microenvironment, consistent with the PD-L1/PD-1 pathway blockade. These data support the continued evaluation of S4-1 as an alternative ICB therapeutic strategy.