Marcus et al. analyzed the role of the cGAS-cGAMP-STING pathway in activating NK cells in the setting of tumors resistant to T cell response and found that NK cell killing of tumor cells was dependent on tumor expression of cGAS and host expression of STING but not cGAS. Mechanistically this suggests that constitutively activated cGAS in the tumor synthesizes cGAMP, which is taken up by non-cancerous host cells where it activates STING and leads to type I IFN production. In patients with melanoma, tumor cGAS expression positively correlated with expression of immune activation genes, NK cell infiltration, and improved survival.

Detection of cytosolic DNA by the enzyme cGAS triggers the production of cGAMP, a second messenger that binds and activates the adaptor protein STING, which leads to interferon (IFN) production. Here, we found that in vivo natural killer (NK) cell killing of tumor cells, but not of normal cells, depends on STING expression in non-tumor cells. Experiments using transplantable tumor models in STING- and cGAS-deficient mice revealed that cGAS expression by tumor cells was critical for tumor rejection by NK cells. In contrast, cGAS expression by host cells was dispensable, suggesting that tumor-derived cGAMP is transferred to non-tumor cells, where it activates STING. cGAMP administration triggered STING activation and IFN-beta production in myeloid cells and B cells but not NK cells. Our results reveal that the anti-tumor response of NK cells critically depends on the cytosolic DNA sensing pathway, similar to its role in defense against pathogens, and identify tumor-derived cGAMP as a major determinant of tumor immunogenicity with implications for cancer immunotherapy.

Author Info: (1) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Division of Immunology and

Author Info: (1) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (2) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (3) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (4) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. (5) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Cancer Research Laboratory, University of California, Berkeley, Berkeley, CA 94720, USA; Immunotherapeutics and Vaccine Research Initiative, University of California, Berkeley, Berkeley, CA 94720, USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: rvance@berkeley.edu. (6) Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Cancer Research Laboratory, University of California, Berkeley, Berkeley, CA 94720, USA; Immunotherapeutics and Vaccine Research Initiative, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: raulet@berkeley.edu.

Less