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However, \u03b1-galactosylceramide (\u03b1GalCer), the prototypical NKT agonist, induces mixed Th1\/Th2 responses with antagonistic cytokine effects, limiting therapeutic selectivity. The development of potent immunostimulatory agents promote Th1 polarization remains a major challenge. Herein, we convert the linear aliphatic chain of \u03b1GalCer into a conformationally constrained all-hydrocarbon macrocyclic scaffold, establishing the first report of a purely hydrocarbon macrocycle pharmacophore. Guided by the structural architecture of the CD1d antigen-binding groove, this design preorganizes the aliphatic chain to optimize A\u2032 pocket occupancy, reduce entropic penalties, and enhance binding stability. \u03b1GalCer macrocyclized (GCC) analogs GCC-1 and GCC-2 elicited potent Th1-biased responses, with an approximately 12-fold increase in in vivo IFN-\u03b3 production relative to \u03b1GalCer, establishing them as highly potent Th1-biased NKT cell agonists. They exhibited potent immunological activity as effective antitumor immunotherapeutic agents and antiviral SARS-CoV-2 vaccine adjuvants, while retaining robust responsiveness in human NKT cells. Collectively, these findings establish the all-hydrocarbon macrocycle as a rational conformational constraint strategy for selectively biasing NKT cell responses, with potential applications in cancer immunotherapy and vaccine development.<\/jats:p>","DOI":"10.1021\/jacsau.6c01038","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:10:04Z","timestamp":1787065804000},"page":"5379-5394","source":"Crossref","is-referenced-by-count":0,"title":["All-Hydrocarbon Macrocycle\nEnables Highly Potent Th1-Biased\nNKT Cell Agonists for Immunotherapy"],"prefix":"10.1021","volume":"6","author":[{"given":"Qian-Nan","family":"Sun","sequence":"first","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wen","sequence":"additional","affiliation":[{"name":"Yangtze University , , ,","place":["Jingzhou, China, 434023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye-Hui","family":"Wu","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"De-Xiang","family":"Mei","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng-Qin","family":"Liu","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Ya","family":"An","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2097-5054","authenticated-orcid":true,"given":"Jun","family":"Guo","sequence":"additional","affiliation":[{"name":"Central China Normal University , , ,","place":["Wuhan, China, 430079"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"issue":"11","key":"2026092808093195400_cit1","doi-asserted-by":"publisher","first-page":"8301","DOI":"10.1097\/JS9.0000000000002993","article-title":"Immunotherapy in central nervous\nsystem tumors","volume":"111","author":"Huang","year":"2025","journal-title":"Int. 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