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The immune targeting of glioblastoma stem cells (GSCs) holds great promise. In this study, structural modifications of the lead compound clofoctol is conducted and structure\u2013activity relationship analyses are performed against GBM, yielding a novel blood\u2010brain barrier\u2010permeable compound,\n                    <jats:bold>B7<\/jats:bold>\n                    , featuring a pivotal multi\u2010substituted diaryl scaffold.\n                    <jats:bold>B7<\/jats:bold>\n                    demonstrates potent anti\u2010GBM effects, significantly inhibiting GSC proliferation, migration, and invasion. Notably,\n                    <jats:bold>B7<\/jats:bold>\n                    inhibits tumor progression, specifically bolstered natural killer (NK) cell\u2010mediated cytotoxicity, and mitigates the immunosuppressive microenvironment in intracranial xenograft mice implanted with GBM cells and GSCs, as well as in cocultures of GSCs and NK\u201092 cells. Mechanistically, these anti\u2010GBM effects of\n                    <jats:bold>B7<\/jats:bold>\n                    are abolished by overexpression of poliovirus receptor cell adhesion molecule (CD155), both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Further exploration reveals that\n                    <jats:bold>B7<\/jats:bold>\n                    targets CD155 via interaction at five crucial binding sites, namely, L47, L108, L142, M110, and V115 residues. These interactions collectively contribute to the hydrophobic interaction energies within the\n                    <jats:bold>B7<\/jats:bold>\n                    \u2010CD155 complex, modulating the CD155\/T cell immunoreceptor with Ig and ITIM domains\/CD226 axis to reshape the NK cell\u2010mediated tumor immune microenvironment. In conclusion, this study establishes the therapeutic potential of\n                    <jats:bold>B7<\/jats:bold>\n                    for glioma, synergistically targeting GSC biology and NK cell immunity for the treatment of GBM.\n                  <\/jats:p>","DOI":"10.1002\/advs.202506688","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T11:08:22Z","timestamp":1749726502000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel Class of Multi\u2010substituted Diaryl Scaffold Derivatives Inhibit Glioblastoma Progression by Targeting CD155"],"prefix":"10.1002","volume":"12","author":[{"given":"Yong\u2010jian","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100050 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