Immunogenic cell death inducer cEmsy boosted cancer immunotherapy in lung adenocarcinoma

Immunogenic cell death (ICD) represents a spectacular approach to boosting tumor immunotherapy by inducing an adaptive immune response, and it is urgent to identify effective and safe ICD inducers. Here, we identified a conserved, ICD-related circular RNA-cEmsy/cEMSY by performing a systematic screening utilizing immunogenic cell death models induced by multiple cell stressors in lung adenocarcinoma (LUAD). cEmsy/cEMSY triggers ICD in LUAD both in vitro and in vivo, leading to the release of damage-associated molecular patterns (DAMPs) and promoting T-cell cross-priming by dendritic cells (DCs). Notably, in the immunosuppressive tumor model, intratumoral delivery of in vitro-transcribed cEmsy encapsulated in lipid nanoparticles (LNP) induces a potent anti-tumor immune response, which synergizes with PD-1 blockade to facilitate long-term cancer immunity with no apparent toxicities. Mechanistically, cEmsy/cEMSY facilitates TDP-43 aggregation in mitochondria and leverages mitochondrial DNA leakage, activating the cGAS-STING pathway and initiating an antiviral immune response. Clinically, elevated expression level of cEMSY correlates with enhanced DCs and CD8+ T cell infiltration, and favorable immunotherapy response in LUAD. Hence, cEmsy/cEMSY emerges as a safe and potent ICD inducer, offering a dual advantage as a mechanism-based target and a biomarker for enhancing ICI responses in LUAD treatment.