AI Article Synopsis

  • The STING (Stimulator of Interferon Genes) pathway plays a crucial role in linking innate immunity to various biological processes, especially in antitumor immunity and maintaining microbiome balance.
  • Researchers discovered a small-molecule STING agonist called SR-717, which is stable and can effectively mimic natural STING ligands, overcoming limitations of earlier cyclic dinucleotide treatments.
  • SR-717 shows promise in cancer therapy by activating immune cells like CD8 T cells and natural killer cells, promoting tumor-fighting mechanisms, and enhancing the expression of important immune markers like PD-L1.

Article Abstract

Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic that induces the same "closed" conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8 T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.

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Source
http://dx.doi.org/10.1126/science.abb4255DOI Listing

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