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Life sciences · Journal article
Acs Chemical Biology · September 23, 2026
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Abstract Toll-like receptor 2 (TLR2) recognizes a remarkably diverse range of microbial molecules and plays central roles in host defense, immune homeostasis, and cancer immunotherapy. Although bacterial lipoproteins and lipopeptides are canonical TLR2 agonists, recent studies have identified additional microbiota-derived ligands, including lipids, proteins, and polysaccharides. Advances in chemical biology, structural analysis, and activity-guided fractionation have revealed how subtle variations in ligand architecture influence TLR2 heterodimer usage, downstream signaling, and context-dependent immune outcomes. In this review, we summarize current knowledge of microbiota-derived TLR2 ligands and discuss recent progress in synthetic TLR2 agonists. We further highlight how ligand structure, receptor heterodimerization, and cellular context collectively shape TLR2-mediated immune responses.