Radiosensitization effect of PD-L1-targeted small molecules with direct antitumor activity on non-small cell lung Cancer.

In this study, we evaluated the combined effects of X-ray irradiation and compounds with PD-L1 downregulation activity (N01-N04) in non-small cell lung cancer (NSCLC) cell lines (HCC78 and H2122), identifying the inhibitor N02 for its superior binding affinity and stability. ELISA assays confirmed that N02 directly blocks the PD-1/PD-L1 interaction with an IC50 of 55.11 ± 6.14 nM. Functional assays, including CCK-8, colony formation, scratch wound healing, and transwell invasion, demonstrated that N02 synergized with radiation to suppress cell viability more potently, clonogenic survival, migration, invasion, and apoptosis compared to either treatment alone. Western blot and qPCR analyses revealed that N02, particularly in combination with radiation, downregulated PD-L1 expression and modulated proteins associated with proliferation and apoptosis. In vivo experiments further validated that the N02-radiation combination significantly inhibited tumor growth. These findings suggest that combining radiotherapy with the compound N02 represents a promising therapeutic strategy to enhance treatment efficacy in NSCLC.