Stimulator of interferon genes (STING) agonists could overcome immunosuppressive microenvironment to improve cancer immunotherapy. However, it is challenging to develop oral STING agonists to achieve systemic immunity. In this study, we discovered ZSA-51 as a potent oral STING agonist with distinct benzo[4,5]thieno[2,3-c]pyrrole-1,3-dione scaffold through tricyclic scaffold screening. ZSA-51, as a prodrug, exhibited nanomolar in vitro STING activation activity and potent in vivo antitumor efficacy in both colon and pancreatic cancer models. The specificity of ZSA-51 in activating STING was confirmed using STING knockout cells and a structurally similar but negative control compound. Moreover, ZSA-51 demonstrated superior oral pharmacokinetic (PK) properties with low toxicity. Importantly, ZSA-51 remodeled immune microenvironment both in tumor and lymph node. Our data suggest that ZSA-51 is a potent oral STING agonist with robust anticancer efficacy, superior PK properties, and low toxicity, holding potential for future development for cancer immunotherapy.