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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.<\/jats:p>","DOI":"10.1021\/acschembio.6c00498","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:02:14Z","timestamp":1790190134000},"page":"2516-2526","source":"Crossref","is-referenced-by-count":1,"title":["Toll-like Receptor 2 Recognition of Microbiota Lipoproteins and Lipids in Immunity and Therapy"],"prefix":"10.1021","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9847-2193","authenticated-orcid":true,"given":"Xing","family":"Zhang","sequence":"first","affiliation":[{"name":"Scripps Research , , , ,","place":["La Jolla, California, United States, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5108-7412","authenticated-orcid":true,"given":"Natavan","family":"Dudkina","sequence":"additional","affiliation":[{"name":"Scripps Research , , , ,","place":["La Jolla, California, United States, 92037"]},{"name":"Scripps Research , , , ,","place":["La Jolla, California, United States, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrianna M.","family":"Turner","sequence":"additional","affiliation":[{"name":"Scripps Research , , , ,","place":["La Jolla, California, United States, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4053-5547","authenticated-orcid":true,"given":"Howard C.","family":"Hang","sequence":"additional","affiliation":[{"name":"Scripps Research , , , ,","place":["La Jolla, California, United States, 92037"]},{"name":"Scripps Research , , , ,","place":["La Jolla, California, United States, 92037"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"issue":"Pt 1","key":"2026101523061780000_cit1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1101\/sqb.1989.054.01.003","article-title":"Approaching the Asymptote? 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