Ten years ago, the second messenger cGAMP was discovered as the activator of the anti-cancer STING pathway. The characterization of cGAMP’s paracrine action and dominant extracellular hydrolase ENPP1 cemented cGAMP as an intercellular immunotransmitter that coordinates the innate and adaptive immune systems to fight cancer. In this Perspective, I look back at a decade of discovery of extracellular cGAMP biology and drug development aiming to supply or preserve extracellular cGAMP for cancer treatment. Reviewing our understanding of the cell type-specific regulatory mechanisms of STING agonists, including their transporters and degradation enzymes, I explain on a molecular and cellular level the successes and challenges of direct STING agonists for cancer therapy. Based on what we know now, I propose new ways to stimulate the STING pathway in a manner that is not only cancer specific, but also cell type specific to fully harness the anti-cancer effect of cGAMP while avoiding collateral damage.

十年前，第二信使 cGAMP 被发现是抗癌 STING 通路的激活剂。 cGAMP 的旁分泌作用和占主导地位的细胞外水解酶 ENPP1 的特性巩固了 cGAMP 作为细胞间免疫递质的地位，可以协调先天性和适应性免疫系统来对抗癌症。在本视角中，我回顾了十年来细胞外 cGAMP 生物学的发现和旨在提供或保存用于癌症治疗的细胞外 cGAMP 的药物开发。回顾我们对 STING 激动剂的细胞类型特异性调节机制（包括其转运蛋白和降解酶）的理解，我在分子和细胞水平上解释了直接 STING 激动剂用于癌症治疗的成功和挑战。根据我们目前所知，我提出了新的方法来刺激 STING 通路，这种方式不仅是癌症特异性的，而且是细胞类型特异性的，以充分利用 cGAMP 的抗癌作用，同时避免附带损害。