Most anticancer immunotherapies that have reached clinical practice have focused on exploiting T cells, the major effectors of the adaptive immune response, with the goal of provoking an immune memory that leads to dramatic, long-lasting effects.
Many pharmaceutical companies are pursuing STING agonists. Although most of the agents are in preclinical or discovery stages, the first clinical trials are under way in combination with checkpoint blockade agents.
Early Warning System
The innate immune response is the frontline of defense against pathogenic invaders, as well as potentially harmful “self” material. These cellular mediators include natural killer cells, macrophages, neutrophils, and dendritic cells that express receptors encoded by genes inherited though the germline, known as pattern recognition receptors (PRRs).
Figure 1. Immune Signaling in the STING Pathway
How the STING Pathway Functions
Current understanding of the STING pathway posits that cGAS senses and binds to cytosolic DNA, triggering a conformational change that activates it. Activated cGAS catalyzes the synthesis of cyclic GMP-AMP (cGAMP) from adenosine triphosphate and guanosine triphosphate. A cyclic dinucleotide (CDN), cGAMP functions as a second messenger, binding to and activating STING, which is found on the membrane of the endoplasmic reticulum.
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