MSA-2 is an orally available human STING agonist.MSA-2 is bound to STING as a noncovalent dimer. Extensive experimental analysis indicates that MSA-2 predimerization is required for binding. Acidic tumor microenvironments favor permeable, uncharged MSA-2. Intracellular MSA-2 is "trapped" and accumulation drives MSA-2 dimerization, preferentially activating STING intratumorally. Orally dosed MSA-2 is well tolerated in mice, exhibiting STING-dependent antitumor activity, as monotherapy and combined with antibodies against PD1 (anti-PD1).