STINGagonister

STINGagonister refers to molecules that activate the Stimulator of Interferon Genes (STING) pathway, eliciting innate immune signaling and type I interferon production. The concept is applied in cancer immunotherapy and vaccine development, where STING pathway activation can stimulate anti-tumor immunity and augment adaptive responses.

Mechanism: In many cells, cytosolic DNA is detected by cGAS, which synthesizes the cyclic dinucleotide cGAMP that binds STING. Activated STING traffics from the endoplasmic reticulum to the Golgi and recruits TBK1, driving phosphorylation of IRF3 and NF-kB and the production of type I interferons and proinflammatory cytokines. STINGagonisters imitate or potentiate this signaling, either by delivering CDN ligands or by using synthetic mimetics that activate human STING.

Types and status: Natural CDNs such as 2'3'-cGAMP and bacterial CDN analogs are prototypical STINGagonisters but face stability and delivery challenges. Synthetic classes include diABZI and amidobenzimidazole derivatives that are active in human STING and can be formulated for intratumoral or systemic use. Several agents have reached clinical evaluation, including ADU-S100 (MIW815) and MK-1454 in combination with checkpoint inhibitors. The older compound DMXAA activated murine STING but failed in human trials due to species differences and insufficient activity.

Safety and challenges: Potential adverse effects include flu-like symptoms and systemic inflammation. Key challenges include achieving tumor-targeted delivery, avoiding excessive cytokine release, overcoming species-specific differences in STING, and identifying responsive patient populations. Ongoing research explores delivery systems, dosing, and combination regimens to maximize efficacy while limiting toxicity.