Functional DNA as a Molecular Tool in Regulating Immunoreceptor–Ligand Interactions

[Image: see text] During immune responses, activating ligands would trigger dynamic spatiotemporal organization of immunoreceptors at the cell interface, governing the fate and effector functions of immune cells. To understand the biophysical mechanisms of immunoreceptor signaling, diverse tools, including DNA technologies, have been developed to manipulate receptor–ligand interactions during the immune activation process. With great capability in the controllable assembly of biomolecules, functional DNA-based precise arrangement of immune molecules at cell interfaces has provided a powerful means in revealing the principles of immunoreceptor triggering, even at the single-molecule level. In addition, precisely regulating immunoreceptor–ligand interactions with functional DNA has been applied in immunotherapies of major diseases. This Perspective will focus on the recent advances in exploring immunoreceptor signaling with functional DNA as the molecular tool as well as the applications of functional DNA mediated regulation of immunoreceptor activation. We also outline the challenges and opportunities of applying functional DNA in immune modulation and immunotherapy.