ArticleiScience2026
STING agonist profiling by nucleotide library defines structural determinants of cyclic dinucleotide recognition.
Article in iScience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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9 authors.
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Abstract
Stimulator of interferon genes (STING) is the principal mammalian receptor for cyclic dinucleotides (CDNs) and a central hub of innate immune signaling. CDN analogues and small-molecule STING agonists are in active development for cancer immunotherapy and as vaccine adjuvants, although clinical translation has proven challenging. Here, we systematically profile STING nucleotide preferences by treating THP-1 monocytes and pancreatic cancer cells with a structurally diverse nucleotide library. We identify 27 CDNs that activate STING, while non-CDN nucleotides failed to elicit detectable responses, underscoring the selectivity of STING for its ligands. We demonstrate that STING's preference for 2'3'-linked CDNs underlies its capacity to accommodate purine-pyrimidine hybrid nucleobases. Molecular dynamics simulations reveal that nucleobase position relative to the 2'3' linkage is a critical determinant of STING engagement. In addition, we show STING activation by diverse non-hydrolysable c-di-AMP and cGAMP isomers, thereby expanding the opportunities for designing STING agonists for therapeutic applications.
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