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. Overall design: To identify the potential ICD inducer derived from circRNAs, whole transcriptome sequencing of stressor-treated(anthracyclines (Doxorubicin), DNA-damaging agents (Oxaliplatin), tyrosine kinase inhibitors ((R)-crizotinib), and platinum-based doublet chemotherapy (Pemetrexed and Cisplatin chemotherapy), alongside proteasomal (Bortezomib) and DNA intercalator (Dactinomycin)) LLC1 cells was analyzed. To investigate the mechanisms by which cEmsy augments ICB therapy efficacy and triggers ICD, we conducted a comprehensive transcriptome analysis on EV and circRNA-overexpressed LLC1 and H358 cell lines.