A novel STING agonist with systemic and durable anti-tumour activity

BackgroundStimulator of interferon genes (STING) has emerged as a crucial and promising target in tumor immunotherapy in recent years. Its agonists play a vital role in activating both innate and adaptive immune responses to combat cancer. Currently, STING agonists are primarily administered through intratumoral or intravenous injection, with only a few could be administered by orally. Therefore, orally available STING agonists are urgently needed to be developed.Approach and resultsBased on previous structure-activity relationship (SAR) studies, we made a structure modification to MSA-2 by replacing the carbonyl group with a difluoromethylene to get a new compound 202 (C202) that exhibited better plasma exposure and oral bioavailability than MSA-2. Thus, we conducted extensive pharmacological evaluations to understand its effects. C202 demonstrated the ability to activate various human STING isoforms and murine STING protein, showcasing a potent and specific activation of the STING signalling pathway at cellular level. In diverse immunocompetent mouse models representing both 'cold' and 'hot' tumors, C202, whether administered intratumorally or orally, displayed broad-spectrum anti-tumor activity. Encouragingly, it induced complete tumor regression in several tumor models of mice and stimulated immune memory effects, contributing to long-term immune response against cancer. Additionally, our investigations into the impact of C202 on the tumor microenvironment found that it enhanced the anti-tumor response of both innate and adaptive immune systems, bolstering the immune-mediated fight against tumors. Furthermore, we made an intriguing observation regarding C202's synergistic effects. It was found to enhance the anti-tumor activity of chemotherapy drug gemcitabine and the angiogenesis inhibitor AL3810, which provide potential combination therapies in future translational studies.ConclusionsOur research highlights C202 as a novel STING agonist with durable anti-tumor activity that can be administered orally, presenting a promising candidate for cancer immunotherapy. C202 specifically activates various STING isoforms and its downstream signalling, and exhibited high oral bioavailability and plasma exposure and displayed broad-spectrum anti-tumor activity either by local or oral administration. C202 activated both innate and adaptive anti-tumor immunity, and importantly it induced complete tumor regression and immune memory,C202 exerts synergistic effects with chemotherapy (gemcitabine) or angiogenesis inhibitor (AL3810) in anti-tumor. # image