The study investigates the role of STING (STimulator of INterferon Genes) as a direct sensor of cyclic dinucleotides (c-di-GMP) in the innate immune system. STING is known to play a crucial role in the production of type I interferons (IFN) in response to cytosolic DNA detection. The authors demonstrate that STING directly binds to c-di-GMP, a second messenger molecule produced by bacteria and archaea, through a specific interaction involving its carboxy-terminal domain (CTD). This binding is competed by unlabelled c-di-GMP but not by other nucleotides or nucleic acids. Additionally, they identify mutations in STING that selectively affect the response to c-di-GMP without affecting the response to DNA. These findings suggest that STING functions as a direct sensor of cyclic dinucleotides, complementing its established role in the interferon response to cytosolic DNA. The study also highlights the potential of cyclic dinucleotides as novel vaccine adjuvants and immunotherapeutics, and provides insights into the mechanisms by which the innate immune system detects bacterial infection.The study investigates the role of STING (STimulator of INterferon Genes) as a direct sensor of cyclic dinucleotides (c-di-GMP) in the innate immune system. STING is known to play a crucial role in the production of type I interferons (IFN) in response to cytosolic DNA detection. The authors demonstrate that STING directly binds to c-di-GMP, a second messenger molecule produced by bacteria and archaea, through a specific interaction involving its carboxy-terminal domain (CTD). This binding is competed by unlabelled c-di-GMP but not by other nucleotides or nucleic acids. Additionally, they identify mutations in STING that selectively affect the response to c-di-GMP without affecting the response to DNA. These findings suggest that STING functions as a direct sensor of cyclic dinucleotides, complementing its established role in the interferon response to cytosolic DNA. The study also highlights the potential of cyclic dinucleotides as novel vaccine adjuvants and immunotherapeutics, and provides insights into the mechanisms by which the innate immune system detects bacterial infection.