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.

Figure 1.. STING pathway signaling and regulation.

A. Cytosolic DNA activates the enzyme cGAS, which produces the cyclic dinucleotide cGAMP that activates STING. Active STING recruits TBK1 and leads to IFN-β transcription downstream of the transcription factors IRF3 and NF-κB. The STING pathway interacts with various other cellular processes, including autophagy (orange), AIM2 inflammasome signaling (green), non-canonical NFκB signaling (blue) and autocrine signaling downstream of IFN-β (maroon). B. Several post-translational modifications regulate cGAS and STING. The modifying factors that promote pathway activation are shown in green boxes, while those that inhibit are shown in red boxes. C. Upon activation by cGAMP, STING traffics from the ER through the ERGIC to perinuclear vesicles prior to lysosomal fusion and degradation. The black arrows show this motion, and the red and green arrows show positive and negative regulation.

Figure 2.. STING pathway activation initiates the anti-tumor immune response.

Endogenous (left side) and pharmacologic (right side) STING agonists elicit similar, but slightly different anti-tumor immune responses. The endogenous immune response involves tumor cell (purple cell) activation of CD11c⁺ cells (orange cells) that leads to type 1 IFN (red dots) signaling and Batf3⁺ DC (red cell) maturation. This, in turn, leads to CD8⁺ T cell (blue cell) cross priming and recruitment by CXCL9/10 (green dots). CD8⁺ T cells can then kill tumor cells (black cells). Treatment with intratumoral STING agonists (green dots) differs because the agonists are membrane permeable and therefore might activate a wider range of cell types including tumor cells, fibroblasts (brown cells), and endothelial cells (red vessels). Pharmacologic agonists also induce endothelial cell death, elicit higher IFN-β expression, and more CD8⁺ T cell cross-priming, which can lead to tumor clearance in preclinical models.