Novel Resorcinol Dibenzyl Ether-Based PD-L1 Inhibitors Modulate Lipid Metabolism for Enhanced Tumor Immunotherapy.

As a critical immune checkpoint molecule, PD-L1 not only suppresses antitumor immunity but also directly promotes tumor progression by reprogramming lipid metabolism. In this study, we designed and synthesized a novel series of compounds by introducing a tail group at the biphenyl core to develop potent small-molecule PD-1/PD-L1 inhibitors. Among these, compound exhibited the highest PD-L1 inhibitory activity (IC = 6.9 nM), significantly surpassing the reference compounds NP19 and BMS-202. Furthermore, demonstrated functional activity by inhibiting lipid accumulation via suppression of the mTOR-SREBP1 pathway, decreasing cholesterol and triglycerides in steatotic HepG2 cells. studies using a HEPA1-6 mouse tumor model revealed that achieved 86.2% tumor growth inhibition at 20 mg/kg, accompanied by enhanced CD3CD8 T-cell infiltration and reduced lipid accumulation in serum. Collectively, represents a promising PD-1/PD-L1 inhibitor with immune- and lipid metabolism-modulating effects, warranting further study as a potential anticancer agent.