The allosteric small-molecule human STING agonist C92 that blocks STING's proton channel is significantly differentiated from orthosteric STING agonists by its unique pharmacology making it a promising immune therapeutic for the treatment of cancer.

We identified distinct residues in SLC7A1 that mediate cGAMP and arginine activity, suggesting that cGAMP transport may be separable from arginine uptake. These findings suggest that modulation of SLC7A1 may influence T cell susceptibility to cGAMP and its analogs.

P1, N=24, Recruiting, Memorial Sloan Kettering Cancer Center

In murine models, prodrugs elicited significantly stronger stimulation in the development of an antitumor immune response compared to the parent CDN 3',3'-c-di-dAMP, as well as the clinically relevant STING agonist ADU-S100. The (Rp,Rp) diastereoisomer exhibited the most pronounced antitumor activity in the context of intravenous administration, significantly suppressing tumor proliferation, extending the survival with a complete response (CR) rate of 90% in a mouse CT26 tumor model, and establishing long-lasting tumor-specific immunological memory. These findings underscore the importance of considering the chirality of phosphotriesters in the development of more effective, safer, and sustainable STING agonist in tumor immunotherapy.

P2, N=120, Not yet recruiting, Shanghai Jeyou Pharmaceutical Co., Ltd.

In vivo, host STING activation with cGAMP-VLP improves the efficacy of immune checkpoint blockade, particularly in tumors lacking cGAS. Together, these findings identify a transcellular mechanism whereby STING activation in dendritic cells increases tumor cell MHC-I expression to enhance CD8+ T cell-mediated tumor recognition.

Using a syngeneic mouse model of genetically engineered Egfr-mutant NSCLC, we evaluated the antitumor effects of STING agonist ADU-S100, alone and combined with osimertinib. Crucially, the combination induced an abscopal effect accompanied by PD-1+/CD8+ cell infiltration. Combining osimertinib with a STING agonist augmented innate and adaptive immunity, inducing systemic antitumor responses in EGFR-mutant NSCLC.

P1, N=12, Not yet recruiting, Daiichi Sankyo Inc.

P1/2, N=248, Completed, Takeda | Active, not recruiting --> Completed

TAK-500 is a novel immune cell-directed antibody-drug conjugate (iADC) composed of TAK-202, an anti-CCR2 monoclonal antibody, conjugated to the STING agonist dazostinag (TAK-676), and is designed to stimulate antitumor immunity by reprogramming CCR2-positive monocytes. These findings demonstrate the feasibility of predicting TAK-500 PK and RO in humans by integrating preclinical and parental antibody clinical data, providing a quantitative framework for first-in-human dose selection of immune cell-directed ADCs. Trial Registration: Clinical trials: NCT04420884, NCT04879849.

P1, N=6, Suspended, University of Maryland, Baltimore | Active, not recruiting --> Suspended | Trial primary completion date: Jan 2026 --> Aug 2025

This study clarified the mechanism underlying the potent antitumor activity of SR-717 in nervous system tumors through activation of the STING-STAT1-HMGN2 signaling pathway and demonstrated that SR-717 has superior efficacy compared to E7766. In addition, HMGN2 was shown to exhibit translational potential as a prognostic biomarker for patient survival.