Targeting HLA‐E in Lung Cancer: The Therapeutic Potential of IRF5‐Engineered M1‐Macrophage‐Derived Exosomes

ABSTRACT Immunotherapy is a pivotal approach in the treatment of lung cancer. Although HLA‐E is a potential target for tumor immunotherapy, its role in lung cancer remains unclear. Previous studies have identified the transcription factor IRF5 as a characteristic gene of M1‐like macrophages, highlighting its crucial role in promoting antitumor immune responses. In this study, we developed an engineered M1‐like macrophage exosomes expressing IRF5 (IRF5 M1‐exos) and demonstrated their ability to inhibit proliferation, migration, and invasion of lung cancer cells. Moreover, our experiments using a nude mouse model revealed that IRF5 M1‐exos exerted potent therapeutic effects by effectively suppressing tumor growth. Notably, the mechanism by which IRF5 exerts its antitumor function through HLA‐E regulation in lung cancer has not been fully elucidated. Here, we identified HLA‐E as a downstream target gene of IRF5 and demonstrated that the overexpression of HLA‐E can counteract the tumor‐promoting effects induced by si‐IRF5 M1‐exos. These results suggest that M1 macrophage‐derived exosomes, enriched with the transcription factor IRF5, exhibit potent antitumor activity by up‐regulating HLA‐E in lung cancer cells. Therefore, IRF5 M1‐exos represent an attractive therapeutic strategy for lung cancer. Schematic illustration of IRF5 M1‐exos: (A) shows the schematic presentation showing the preparation process of IRF5 M1‐exos; (B) shows the scheme showing the effects of IRF5 M1‐exos against cancer; and (C) shows the mechanism of anticancer effect of IRF5 M1‐exos.