Polyvalent design in the cGAS-STING pathway.

Polyvalent interactions mediate the formation of higher-order macromolecular assemblies to improve the sensitivity, specificity, and temporal response of biological signals. In host defense, innate immune pathways recognize danger signals to alert host of insult or foreign invasion, while limiting aberrant activation from auto-immunity and cellular senescence. Of recent attention are the unique higher-order assemblies in the cGAS-STING pathway. Natural stimulation of cGAS enzymes by dsDNA induces phase separation and enzymatic activation for switchlike production of cGAMP. Subsequent binding of cGAMP to STING induces oligomerization of STING molecules, offering a scaffold for kinase assembly and signaling transduction. Additionally, the discovery of PC7A, a synthetic polymer which activates STING through a non-canonical biomolecular condensation, illustrates the engineering design of agonists by polyvalency principles. Herein, we discuss a mechanistic and functional comparison of natural and synthetic agonists to advance our understanding in STING signaling and highlight the principles of polyvalency in innate immune activation. The combination of exogenous cGAMP along with synthetic PC7A stimulation of STING offers a synergistic strategy in spatiotemporal orchestration of the immune milieu for a safe and effective immunotherapy against cancer.