The circRNA cEMSY Induces Immunogenic Cell Death and Boosts Immunotherapy Efficacy in Lung Adenocarcinoma

Abstract Immunogenic cell death (ICD) induces an active immune response. Activating ICD represents a potential approach to boost the antitumor activity of immunotherapy, highlighting the need to identify effective and safe ICD inducers. In this study, we identified a conserved, ICD-related circular RNA cEMSY by systematically screening ICD models induced by multiple cell stressors in lung adenocarcinoma. cEMSY triggered ICD in lung adenocarcinoma cells both in vitro and in vivo, leading to the release of damage-associated molecular patterns and promoting T-cell cross-priming by dendritic cells. Notably, the intratumoral delivery of lipid nanoparticle–encapsulated cEMSY induced a potent antitumor immune response in an immunosuppressed tumor model, which synergized with PD-1 blockade to facilitate long-term antitumor immunity with no apparent toxicities. Mechanistically, cEMSY mediated mitochondrial aggregation of the RNA-binding protein TDP-43 that enabled leakage of mitochondrial DNA to stimulate the cGAS–STING pathway, activating the antiviral immune response. Clinically, elevated expression of cEMSY correlated with enhanced infiltration of dendritic cells and CD8+ T cells and favorable immunotherapy response in lung adenocarcinoma. Together, these findings support the dual potential of cEMSY as a target and biomarker for improving immune checkpoint inhibitor responses in lung adenocarcinoma. Significance: cEMSY is a safe and effective immunogenic cell death inducer that synergizes with PD-1 blockade in lung adenocarcinoma, providing a potential strategy to enhance the efficacy of tumor immunotherapy.