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

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Programmed death-ligand 1 (PD-L1) on tumor-derived small extracellular vesicles (sEVs) can impede anti-cancer immune responses by engaging PD-1 on immune cells.
• Enhancing immunotherapy efficacy by targeting sEV PD-L1 secretion is a promising strategy, but lacks small-molecule inhibitors for clinical use.

Purpose of the Study:

• To identify novel small-molecule inhibitors targeting the secretion of PD-L1 on sEVs.
• To evaluate the therapeutic potential of identified inhibitors in preclinical cancer models.

Main Methods:

• A dual high-throughput screening strategy combining virtual screening and nanoflow-based experimental verification was employed.
• Ibuprofen (IBP) was identified as an inhibitor disrupting PD-L1+ sEV biogenesis and secretion.
• Mechanism of action was elucidated through interaction with hepatocyte growth factor-regulated tyrosine kinase substrate.

Main Results:

• Ibuprofen was identified as a novel inhibitor of sEV PD-L1 secretion, acting via a mechanism distinct from its known cyclooxygenase targets.
• IBP administration stimulated antitumor immunity and potentiated anti-PD-1 therapy efficacy in melanoma and oral squamous cell carcinoma mouse models.
• A topical IBP gel formulation combined with anti-PD-1 treatment showed significant therapeutic efficacy.

Conclusions:

• Ibuprofen is a promising small-molecule inhibitor targeting sEV PD-L1 secretion, offering a new strategy to enhance immunotherapy.
• The findings provide a foundation for developing durable, systemic antitumor immunity through novel therapeutic approaches.