Novel Small-Molecule PD-L1 Inhibitor Induces PD-L1 Internalization and Optimizes the Immune Microenvironment

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.