cGAS is essential for the antitumor effect of immune checkpoint blockade

Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1637-1642. doi: 10.1073/pnas.1621363114. Epub 2017 Jan 30.


cGMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses. cGAS catalyzes the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce type I interferons (IFNs) and other immune modulatory molecules. Here we show that cGAS is indispensable for the antitumor effect of immune checkpoint blockade in mice. Wild-type, but not cGAS-deficient, mice exhibited slower growth of B16 melanomas in response to a PD-L1 antibody treatment. Consistently, intramuscular delivery of cGAMP inhibited melanoma growth and prolonged the survival of the tumor-bearing mice. The combination of cGAMP and PD-L1 antibody exerted stronger antitumor effects than did either treatment alone. cGAMP treatment activated dendritic cells and enhanced cross-presentation of tumor-associated antigens to CD8 T cells. These results indicate that activation of the cGAS pathway is important for intrinsic antitumor immunity and that cGAMP may be used directly for cancer immunotherapy.

Keywords: PD-L1; STING; cGAMP; cGAS; cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / administration & dosage
  • Antibodies / immunology
  • Antibodies / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Cross-Priming / drug effects
  • Cross-Priming / immunology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Immunity, Innate / drug effects
  • Immunity, Innate / immunology*
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleotides, Cyclic / administration & dosage
  • Nucleotides, Cyclic / immunology*
  • Nucleotides, Cyclic / pharmacology
  • Nucleotidyltransferases / genetics
  • Nucleotidyltransferases / immunology*
  • Nucleotidyltransferases / metabolism
  • Survival Analysis


  • Antibodies
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Nucleotides, Cyclic
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Nucleotidyltransferases
  • cGAS protein, mouse