STING agonists as next-generation vaccine adjuvants: mechanisms, opportunities, and challenges

Vaccine adjuvants shape the magnitude and quality of adaptive immune responses by engaging innate sensing pathways. Among emerging platforms, agonists of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway have gained significant attention due to their capacity to induce type I interferon responses, enhance antigen cross-presentation, and promote robust CD4⁺ and CD8⁺ T cell immunity. This review outlines the major classes of natural and synthetic STING agonists, their mechanisms of action, and their applications as vaccine adjuvants and stand-alone immunoprophylactic agents, with a particular focus on viral infections and virus-associated cancers. We also discuss their roles in cancer immunotherapy and highlight key translational challenges, including species-specific differences, human STING polymorphisms, and safety considerations related to excessive or prolonged pathway activation. Finally, we summarize emerging strategies aimed at optimizing STING agonist design, delivery, and precision targeting to improve safety and efficacy in next-generation vaccine and immunotherapy development.