STING pathway agonism as a cancer therapeutic

Abstract

The fact that a subset of human cancers showed evidence for a spontaneous adaptive immune response as reflected by the T cell-inflamed tumor microenvironment phenotype led to the search for candidate innate immune pathways that might be driving such endogenous responses. Preclinical studies indicated a major role for the host STING pathway, a cytosolic DNA sensing pathway, as a proximal event required for optimal type I interferon production, dendritic cell activation, and priming of CD8⁺ T cells against tumor-associated antigens. STING agonists are therefore being developed as a novel cancer therapeutic, and a greater understanding of STING pathway regulation is leading to a broadened list of candidate immune regulatory targets. Early phase clinical trials of intratumoral STING agonists are already showing promise, alone and in combination with checkpoint blockade. Further advancement will derive from a deeper understanding of STING pathway biology as well as mechanisms of response vs resistance in individual cancer patients.

Keywords: STimulator of INterferon Genes; cancer immunotherapy; innate immunity; tumor immunity; type I interferon.