The carcinogenic metabolite acetaldehyde impairs cGAS activity to negatively regulate antiviral and antitumor immunity.

Abstract

The cGAS-MITA/STING pathway plays critical roles in both host defense against DNA virus and intrinsic antitumor immunity by sensing viral genomic DNA or dis-located mitochondrial/cellular DNA. Whether carcinogenic metabolites can target the cGAS-MITA axis to promote tumorigenesis is unknown. In this study, we identified acetaldehyde, a carcinogenic metabolite, as a suppressor of the cGAS-MITA pathway. Acetaldehyde inhibits the DNA virus herpes simplex virus 1 (HSV-1)- and transfected DNA-triggered but not cGAMP-induced activation of downstream components and induction of downstream effector genes. Mechanistically, acetaldehyde impairs the binding of cGAS to DNA as well as the phase separation of the cGAS-DNA complex in cells. In mouse models, acetaldehyde inhibits antiviral cytokine production, promotes viral replication and lethality upon HSV-1 infection. In a colorectal tumor xenograft model, acetaldehyde promotes tumor growth and inhibits CD8⁺ T cell infiltration by targeting cGAS in both the tumor cells and immune cells in mice. Bioinformatic analysis indicates that expression of acetaldehyde dehydrogenase 2 (ALDH2), which converts acetaldehyde to acetic acid, is negatively correlated with stimulatory immune signatures in clinical colorectal tumors, and higher ALDH2 expression exhibits better prognosis of colorectal cancer patients. Collectively, our results suggest that acetaldehyde impairs cGAS activity to inhibit the cGAS-MITA axis, which contributes to its effects on carcinogenesis.