Structure-guided approaches to modulate endosomal toll-like receptors TLR7, TLR8 and TLR9: advances, challenges and therapeutic promise

Abstract

TLR7, TLR8 and TLR9 are endosomal immune receptors central to antiviral defense, autoimmunity and cancer immunotherapy. Recent structural insights have revealed distinct ligand-binding mechanisms and conformational dynamics, enabling the design of selective small-molecule agonists and antagonists. This review summarizes key advances in TLR7/8/9 biology, pharmacology and structure-guided drug discovery. We highlight clinical progress, delivery strategies and translational challenges including species-specific differences and immune-related toxicities. Novel approaches such as nanoparticle systems and endogenous RNA mimetics promise targeted modulation of TLR activity. Together, these developments emphasize the therapeutic potential of precision TLR modulation in immunologically complex diseases.