2020/08/21 by Bo‐Sheng Pan, Samanthi A. Perera, Jennifer Piesvaux +38 · 3 citations
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · Medicine · #RNA modifications and cancer #Viral Infections and Vectors #interferon and immune responses
paper · doi:10.1126/science.aba6098
openalex publication_date 2020/08/21 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
Pharmacological activation of the STING (stimulator of interferon genes)-controlled innate immune pathway is a promising therapeutic strategy for cancer. Here we report the identification of MSA-2, an orally available non-nucleotide human STING agonist. In syngeneic mouse tumor models, subcutaneous and oral MSA-2 regimens were well tolerated and stimulated interferon-β secretion in tumors, induced tumor regression with durable antitumor immunity, and synergized with anti-PD-1 therapy. Experimental and theoretical analyses showed that MSA-2 exists as interconverting monomers and dimers in solution, but only dimers bind and activate STING. This model was validated by using synthetic covalent MSA-2 dimers, which were potent agonists. Cellular potency of MSA-2 increased upon extracellular acidification, which mimics the tumor microenvironment. These properties appear to underpin the favorable activity and tolerability profiles of effective systemic administration of MSA-2.