title: Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response.
abstract: Immunotherapy is one of the key strategies for cancer treatment. The cGAS-cGAMP-STING-IRF3 pathway of cytosolic DNA sensing plays a pivotal role in antiviral defense. We report that the STING activator cGAMP possesses significant antitumor activity in mice by triggering the STING-dependent pathway directly. cGAMP enhances innate immune responses by inducing production of cytokines such as interferon-β, interferon-γ, and stimulating dendritic cells activation, which induces the cross-priming of CD8(+) T cells. The antitumor mechanism of cGAMP was verified by STING and IRF3, which were up-regulated upon cGAMP treatment. STING-deficiency dramatically reduced the antitumor effect of cGAMP. Furthermore, cGAMP improved the antitumor activity of 5-FU, and clearly reduced the toxicity of 5-FU. These results demonstrated that cGAMP is a novel antitumor agent and has potential applications in cancer immunotherapy.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Tiejun
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Chemistry &Shanghai Key Laboratory of Chemical Biology for Protein Research and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Department of Chemistry &Shanghai Key Laboratory of Chemical Biology for Protein Research and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Chemistry &Shanghai Key Laboratory of Chemical Biology for Protein Research and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Shu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Yuefan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry &Shanghai Key Laboratory of Chemical Biology for Protein Research and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.
authors.forename: Pengbiao
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Yaocheng
authors.initials: Y
authors.lastname: Rui
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Pingwei
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Chemistry &Shanghai Key Laboratory of Chemical Biology for Protein Research and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200433, China.
authors.forename: Xiangshi
authors.initials: X
authors.lastname: Tan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology / Q000633:toxicity; D007113:Immunity, Innate / Q000187:drug effects*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D009713:Nucleotidyltransferases / Q000378:metabolism*; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D005472:Fluorouracil; D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D009713:Nucleotidyltransferases; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase