piSTING: A Pocket‐Independent Agonist Based on Multivalency‐Driven STING Oligomerization

Abstract The stimulator of interferon genes (STING) pathway is a potent therapeutic target for innate immunity. Despite the efforts to develop pocket‐dependent small‐molecule STING agonists that mimic the endogenous STING ligand, cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), most of these agonists showed disappointing results in clinical trials owing to the limitations of the STING pocket. In this study, we developed novel pocket‐independent STING‐activating agonists (piSTINGs), which act through multivalency‐driven oligomerization to activate STING. Additionally, a piSTING‐adjuvanted vaccine elicited a significant antibody response and inhibited tumour growth in therapeutic models. Moreover, a piSTING‐based vaccine combination with aPD‐1 showed remarkable potential to enhance the effectiveness of immune checkpoint blockade (ICB) immunotherapy. In particular, piSTING can strengthen the impact of STING pathway in immunotherapy and accelerate the clinical translation of STING agonists.