Related Experiment Video
Updated: Mar 10, 2026
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Novel Resorcinol Dibenzyl Ether-Based PD-L1 Inhibitors Modulate Lipid Metabolism for Enhanced Tumor Immunotherapy
Zichao Yang1, Ziqing Liu1,2, Jiayi Zhou1
1Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Abstract:
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 ZQ8 exhibited the highest PD-L1 inhibitory activity (IC50 = 6.9 nM), significantly surpassing the reference compounds NP19 and BMS-202. Furthermore, ZQ8 demonstrated functional activity by inhibiting lipid accumulation via suppression of the mTOR-SREBP1 pathway, decreasing cholesterol and triglycerides in steatotic HepG2 cells. In vivo studies using a HEPA1-6 mouse tumor model revealed that ZQ8 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, ZQ8 represents a promising PD-1/PD-L1 inhibitor with immune- and lipid metabolism-modulating effects, warranting further study as a potential anticancer agent.
Insights
A novel compound, ZQ8, effectively inhibits PD-1/PD-L1, suppressing tumor growth and reprogramming lipid metabolism. This small-molecule inhibitor shows promise as an anticancer agent by enhancing T-cell infiltration and reducing lipid accumulation.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint molecule that suppresses antitumor immunity.
- PD-L1 also directly promotes tumor progression by reprogramming cellular lipid metabolism.
- Targeting PD-L1 offers a potential strategy for cancer therapy.
Purpose of the Study:
- To design and synthesize novel small-molecule inhibitors targeting PD-1/PD-L1.
- To evaluate the efficacy of these compounds in inhibiting PD-L1 activity and modulating lipid metabolism.
- To assess the antitumor potential of the lead compound in preclinical models.
Main Methods:
- Synthesis of novel biphenyl compounds with tail group modifications.
- Biochemical assays to determine PD-L1 inhibitory activity (IC50).
- Cell-based assays to assess lipid accumulation and pathway modulation (mTOR-SREBP1).
- In vivo studies using a HEPA1-6 mouse tumor model to evaluate tumor growth inhibition and immune cell infiltration.
Main Results:
- Compound ZQ8 exhibited potent PD-L1 inhibition (IC50 = 6.9 nM), outperforming reference compounds.
- ZQ8 suppressed lipid accumulation by inhibiting the mTOR-SREBP1 pathway in steatotic HepG2 cells.
- In vivo, ZQ8 achieved 86.2% tumor growth inhibition, increased CD3+CD8+ T-cell infiltration, and reduced serum lipid levels.
Conclusions:
- ZQ8 is a potent small-molecule inhibitor of PD-1/PD-L1.
- ZQ8 possesses dual activity: immune modulation and lipid metabolism reprogramming.
- ZQ8 demonstrates significant antitumor efficacy and warrants further investigation as a potential anticancer therapeutic.
