Nanocarrier-enabled STING agonist delivery for enhanced cancer immunotherapy

The innate immune system serves as the first line of defense against pathogens, with the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway emerging as a critical target for cancer immunotherapy. This pathway triggers potent antitumor immunity through the production of type I interferons and other inflammatory mediators, making it a focal point in cancer research. However, the clinical application of free STING agonists faces significant challenges, including rapid systemic clearance, poor bioavailability, non-specific activation, and dose-limiting toxicities. Nanocarrier-based delivery systems offer a promising solution to these limitations. By optimizing nanoparticle size, charge, and surface characteristics, these systems can encapsulate and protect STING agonists, thereby enhancing their stability and prolonging circulation time. Moreover, nanocarriers enable targeted delivery to tumor tissues and immune cells, minimizing off-target effects and improving therapeutic efficacy while reducing toxicity. This review provides an overview of the cGAS-STING signaling mechanism and the current development landscape of STING agonists. It critically examines the advantages and limitations of these agonists, with a focus on nanocarrier-mediated delivery platforms. Finally, we discuss the challenges and future directions for advancing nano-STING therapy, highlighting the need for continued research to overcome existing scientific and translational barriers and fully realize its clinical potential.