干扰素基因刺激剂
细胞生物学
肿瘤微环境
信号转导
生物
细胞外
癌症研究
先天免疫系统
免疫学
免疫系统
肿瘤细胞
作者
Vera E. Mekers,Vera M. Kho,Marleen Ansems,Gosse J. Adema
标识
DOI:10.1016/j.radonc.2022.07.014
摘要
Cyclic GMP-AMP synthase (cGAS), second messenger 2'3'-cyclic GMP-AMP (cGAMP) and stimulator of interferon genes (STING) are fundamental for sensing cytoplasmic double stranded DNA. Radiotherapy treatment induces large amounts of nuclear and mitochondrial DNA damage and results in the presence of DNA fragments in the cytoplasm, activating the cGAS/STING pathway. Triggering of the cGAS/STING pathway in the tumor microenvironment (TME) results in the production of type I interferons (IFNs). Type I IFNs are crucial for an effective antitumor defense, with myeloid cells as key players. Many questions remain on how these myeloid cells are activated and in which cells (tumor versus myeloid) in the TME the signaling pathway is initiated. The significance of cGAS/STING signaling in the onco-immunology field is being recognized, emphasized by the frequent occurrence of mutations in or silencing of genes in this pathway. We here review several mechanisms of cGAS/STING signal propagation in the TME, focusing on tumor cells and myeloid cells. Cell-cell contact-dependent interactions facilitate the transfer of tumor-derived DNA and cGAMP. Alternatively, transport routes via the extracellular space such as extracellular vesicles, and channel-mediated cGAMP transfer to and from the extracellular space contribute to propagation of cGAS/STING signal mediators DNA and cGAMP. Finally, we discuss regulation of extracellular cGAMP. Altogether, we provide a comprehensive overview of cGAS/cGAMP/STING signal propagation from tumor to myeloid cells in the TME, revealing novel targets for combinatorial treatment approaches with conventional anticancer therapies like radiotherapy.
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