Cancer-Cell-Intrinsic cGAS Expression Mediates Tumor Immunogenicity

Cell Rep. 2019 Oct 29;29(5):1236-1248.e7. doi: 10.1016/j.celrep.2019.09.065.


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 cytoplasmic DNA, they rarely produce type I IFN spontaneously. 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 genotoxic treatments and immunotherapy. Thus, cancer-cell-derived cGAMP is 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.

Keywords: CD8(+) T cells; STING; cGAMP; cGAS; cancer; chemotherapy; gap junctions; immunotherapy; radiotherapy; type I IFN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • DNA Damage
  • Dendritic Cells / metabolism
  • Disease Progression
  • Humans
  • Immunotherapy
  • Interferon Type I / metabolism
  • Membrane Proteins
  • Mice, Inbred C57BL
  • Microsatellite Repeats / genetics
  • Neoplasms / drug therapy
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Nucleotides, Cyclic / metabolism
  • Nucleotidyltransferases / metabolism*


  • Interferon Type I
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Sting1 protein, mouse
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Nucleotidyltransferases
  • cGAS protein, human
  • cGAS protein, mouse