Loss of ADAR1 in lung cancer activates anti-tumour immunity and suppresses tumour cell growth via the RIG-I/MDA5-MAVS pathway.

Abstract

Aberrant accumulation of dsDNA in tumour cells activates the cGAS-STING pathway, playing a crucial role in anti-tumour immunity. However, the role of the dsRNA sensor RIG-I-like receptor-mitochondrial antiviral signalling protein (RLR-MAVS) in anti-tumour immunity remains unclear. ADAR1 edits endogenous dsRNA by catalysing the deamination of adenosine to inosine, preventing activation of the RLR-MAVS pathway, which is vital for immune homeostasis and tissue development. In this study, we investigated the roles of ADAR1 and RLR-MAVS in anti-tumour immunity of lung cancer. Our findings revealed that knockout Adar1 induces dsRNA accumulation, activating the TBK1-IRF3 pathway and stimulating interferon stimulating genes (ISGs) expression, which in turn activates anti-tumour immunity and suppresses lung cancer growth. We demonstrated that the RIG-I/MDA5-MAVS pathway is responsible for this anti-tumour immune activation and tumour suppression, which is contrast to the effects mediated by Zbp1, another downstream molecule regulated by Adar1, which is known to drive lethal type I interferon activation and immunopathology inflammatory responses. Moreover, we found that Adar1-deficient lung cancer cells suppress abscopal homogeneous and non-homogeneous tumour growth when used as a tumour cell vaccine. Additionally, Adar1 deficiency in lung cancer cells significantly enhances the efficacy of immunotherapy when employed as adjuvant. In summary, our study elucidates the mechanism by which Adar1 deficiency activates anti-tumour immunity and inhibits tumour cell growth. These findings highlight Adar1 and the downstream RIG-I/MDA5-MAVS pathway as promising targets for immunotherapy development.