Stimulating STING for cancer therapy: Taking the extracellular route.

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.