Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity

Sensing of cytoplasmic DNA by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) results in production of the dinucleotide cGAMP and consecutive activation of stimulator of interferon genes (STING) followed by production of type I interferon (IFN). Although cancer cells contain supra-normal concentrations of cyto-plasmicDNA, they rarely producetype I IFNspontaneously. This suggests that defects in the DNA-sensing pathway may serve as an immune escape mechanism. We find that cancer cells produce cGAMP that is transferred via gap junctions to tumor-associated dendritic cells (DCs) and macrophages, which respond by producing type I IFN in situ. Cancer-cell-intrinsic expression of cGAS, but not STING, promotes infiltration by effector CD8(+) T cells and consequently results in prolonged survival. Furthermore, cGAS-expressing cancers respond better to geno-toxic treatments and immunotherapy. Thus, cancer-cell-derived cGAMPis crucial to protective anti-tumor CD8(+) T cell immunity. Consequently, cancer-cell-intrinsic expression of cGAS determines tumor immunogenicity and makes tumors hot. These findings are relevant for genotoxic and immune therapies for cancer.