Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate Immune Response

• DOI: 10.1038/srep19049
• Publication Date: 2016-01-12T09:47:29Z
• Authors: Tiejun Li; Hao Cheng; Hong Yuan; Qiming Xu; Chang Shu; Yuefan Zhang; Pengbiao Xu; Jason Tan; Yaocheng Rui; Pingwei Li; Xiangshi Tan
• Keywords: Mice, Inbred BALB C; 0303 health sciences; Membrane Proteins; Antineoplastic Agents; Apoptosis; Dendritic Cells; Nucleotidyltransferases; Article; Immunity, Innate; 3. Good health; 03 medical and health sciences; Cell Line, Tumor; Animals; Cytokines; Interferon Regulatory Factor-3; Fluorouracil; Nucleotides, Cyclic

AbstractImmunotherapy 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.