In a pair of studies, researchers report the discovery and molecular pharmacology of stable, synthetic STING (stimulator of interferon genes) agonists that induce anticancer immune responses in mice. Combined, both studies' results represent progress towards clinically viable STING agonists for future cancer drugs and immunotherapeutic strategies. Activation of the innate STING immune pathway by natural agonists has been demonstrated to play an important role in antitumor immunity, which has made them an attractive target for use in cancer therapies. It's suggested that the administration of synthetic agonists of the STING pathway could be used to trigger de novo anticancer immune responses that can control tumor growth or enhance the outcome of cancer treatments like PD-1 blockade immunotherapy. However, the development of STING agonists for drug development has been challenging and largely limited by the inherent instability of the molecules involved. Here, Emily Chin and colleagues and Bo-Sheng Pan and colleagues, respectively, report on the discovery of stable STING agonists that show antitumor activity in preclinical cancer models. Chin et al. describe SR-717 - a stable, non-nucleotide small molecule STING agonist that functions similarly to the natural STING ligand cGAMP. According to these authors, SR-717 demonstrated robust anti-tumor activities in a mouse model of melanoma. Building on these findings, Pan et al. developed an agonist capable of pharmacologically activating the STING immune pathway through an orally administered drug. When tested in mouse models, the authors found that it was able to induce tumor regression and improve checkpoint blockade therapy. "Non-nucleotide small-molecule STING agonists that can be administered systemically may represent an attractive approach for targeting this pathway and have the potential to transform the therapeutic landscape once optimized," write Thomas Gajewski and Emily Higgs in a related Perspective.
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Journal
Science