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 <b>ZQ8</b> exhibited the highest PD-L1 inhibitory activity (IC₅₀ = 6.9 nM), significantly surpassing the reference compounds NP19 and BMS-202. Furthermore, <b>ZQ8</b> demonstrated functional activity by inhibiting lipid accumulation via suppression of the mTOR-SREBP1 pathway, decreasing cholesterol and triglycerides in steatotic HepG2 cells. <i>In vivo</i> studies using a HEPA1-6 mouse tumor model revealed that <b>ZQ8</b> achieved 86.2% tumor growth inhibition at 20 mg/kg, accompanied by enhanced CD3⁺CD8⁺ T-cell infiltration and reduced lipid accumulation in serum. Collectively, <b>ZQ8</b> represents a promising PD-1/PD-L1 inhibitor with immune- and lipid metabolism-modulating effects, warranting further study as a potential anticancer agent.