Targeting toll-like receptors in the immunotherapy era: the chemistry behind TLR modulators

Toll-like receptors (TLRs) comprise a family of transmembrane pattern-recognition receptors that sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), thereby orchestrating innate immune responses. Over the past decade, TLRs have emerged as promising therapeutic targets for infectious, inflammatory, autoimmune, and oncological diseases. This review provides a comprehensive overview of TLR agonists and antagonists reported in the last ten years, highlighting an exceptional range of chemical classes, including peptides, nucleic acids, glycolipids, lipopeptides, and small molecules. We discuss the structural determinants underlying receptor selectivity, the design strategies enabling functional modulation, and the progress in preclinical and clinical development. We also address emerging trends, remaining challenges, and opportunities for the rational design of next-generation TLR modulators with improved selectivity and therapeutic potential.