Department of Chemistry, Stanford University, Stanford, CA, USA.
Stanford ChEM-H, Stanford University, Stanford, CA, USA.
Nat Cancer. 2020 Feb;1(2):184-196. doi: 10.1038/s43018-020-0028-4. Epub 2020 Feb 24.
2'3'-cyclic GMP-AMP (cGAMP) is an intracellular second messenger that is synthesized in response to cytosolic double-stranded DNA and activates the innate immune STING pathway. Our previous discovery of its extracellular hydrolase ENPP1 hinted at the existence of extracellular cGAMP. Here, we detected that cGAMP is continuously exported but then efficiently cleared by ENPP1, explaining why it has previously escaped detection. By developing potent, specific, and cell impermeable ENPP1 inhibitors, we found that cancer cells continuously export cGAMP in culture at steady state and at higher levels when treated with ionizing radiation (IR). In mouse tumors, depletion of extracellular cGAMP decreased tumor-associated immune cell infiltration and abolished the curative effect of IR. Boosting extracellular cGAMP with ENPP1 inhibitors synergized with IR to delay tumor growth. In conclusion, extracellular cGAMP is an anti-cancer immunotransmitter that could be harnessed to treat cancers with low immunogenicity.
2'3'-环鸟苷酸-腺苷酸（cGAMP）是一种细胞内的第二信使，它在细胞质中的双链 DNA 反应下合成，并激活先天免疫 STING 通路。我们之前发现其细胞外水解酶 ENPP1 暗示了细胞外 cGAMP 的存在。在这里，我们检测到 cGAMP 不断被输出，但随后被 ENPP1 有效清除，这解释了为什么它之前没有被检测到。通过开发有效的、特异性的、细胞不可渗透的 ENPP1 抑制剂，我们发现癌细胞在培养物中以稳定状态连续输出 cGAMP，并且在用电离辐射（IR）处理时输出水平更高。在小鼠肿瘤中，耗尽细胞外 cGAMP 会减少肿瘤相关免疫细胞浸润，并消除 IR 的治疗效果。用 ENPP1 抑制剂增强细胞外 cGAMP 与 IR 协同作用，延缓肿瘤生长。总之，细胞外 cGAMP 是一种抗癌免疫递质，可以被利用来治疗免疫原性低的癌症。
