Discovery of Dual PD-L1/HDAC3 Inhibitors for Tumor Immunotherapy

Targeting programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has been considered as one of the most promising strategies for tumor immunotherapy. However, single-target PD-1/PD-L1 inhibitors frequently exhibit limited efficacy, highlighting the urgent need for new therapies. Herein, a series of dual PD-L1/HDAC3 inhibitors were developed through a pharmacophore fusion strategy for the first time. Among them, compound PH3 was identified as the most promising dual PD-L1/HDAC3 inhibitor, with potent PD-1/PD-L1 inhibitory activity (IC₅₀ = 89.4 nM) and selective HDAC3 inhibitory activity (IC₅₀ = 107 nM). Moreover, PH3 exhibited superior in vitro antitumor activities and in vitro immune activation effects. Additionally, PH3 showed potent and dose-dependent antitumor efficacy in the B16-F10 melanoma mouse model without obvious toxicity. Furthermore, PH3 increased the infiltration of CD3⁺CD8⁺ and CD3⁺CD4⁺ cells in the tumor microenvironment. Collectively, PH3 represented a novel dual PD-L1/HDAC3 inhibitor deserving further investigation as a tumor immunotherapy agent.