Multiple studies have identified the STING (stimulator of interferon genes) pathway as a critical mechanism of innate immune sensing of cytoplasmic foreign or self-DNA, that drives type-I interferons (IFNs) production and promotes robust antitumor responses. STING is directly activated by cGAMP cyclic dinucleotides (CDNs) derived from cytosolic dsDNA (self or foreign) through the action of cyclic GMP-AMP synthase (cGAS). Activation of STING leads to the phosphorylation and activation of the transcription factor IRF3, via TBK1 activity. IRF3 translocates to the nucleus and promotes the expression of type I interferon genes, such as IFN-β, which leads to interferon β production that facilitates T cell priming, in such a way that STING agonists can be used as stimulants for anticancer immune activity. Currently a number of synthetic CDNs are in Phase I and II clinical trials in which the drugs are administered by local injection. Our research focuses on next generation small molecule STING agonists that can potentially be administered systemically. Our objective was to identify and develop novel small molecule activators of the STING pathway as potential new anti-cancer agents. By undertaking a phenotypic high throughput chemical screening (HTCS) campaign of 270,000 compounds using an IRF3-luciferase reporter cell line, we successfully identified both direct agonists and indirect activators of STING. Here we present the details and outcomes of our screening effort, and preliminary characterization of an indirect STING activator, CTX-485.