High-throughput screening identifies ibuprofen as an sEV PD-L1 inhibitor for synergistic cancer immunotherapy.

ABSTRACT: Programmed death-ligand 1 (PD-L1) on tumor-derived small extracellular vesicles (sEVs) limits therapeutic effectiveness by interacting with the PD-1 receptor on host immune cells. Targeting the secretion of sEV PD-L1 has emerged as a promising strategy to enhance immunotherapy. However, the lack of small-molecule inhibitors poses a challenge for clinical translation. In this study, we developed a target and phenotype dual-driven high-throughput screening strategy that combined virtual screening with nanoflow-based experimental verification. We identified ibuprofen (IBP) as a novel inhibitor that effectively targeted sEV PD-L1 secretion. IBP disrupted the biogenesis and secretion of PD-L1⁺ sEVs in tumor cells by physically interacting with a critical regulator of sEV biogenesis,

SUBMITTER: Chen ZK 

PROVIDER: S-EPMC11489553 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature