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While synthetic Sia derivatives can manipulate the Sia\u2010Siglec axis with high affinity, their therapeutic application has been hampered by the poor substrate tolerance of wild\u2010type CMP\u2010sialic acid synthase (CSS) for sterically demanding analogs. Here, we report a structure\u2010guided engineering strategy to evolve\n                    <jats:italic>Neisseria meningitidis<\/jats:italic>\n                    CMP\u2010Sia synthetase (NmCSS) for enhanced activity with bulky substrates. Coupling this optimized NmCSS variant with a sialyltransferase enabled a scalable \u201cone\u2010pot two\u2010enzyme\u201d (OPTE) synthesis of diverse sialoside analogs. Screening this library on glycan microarrays revealed novel high\u2010affinity ligands with selective Siglec binding profiles. Leveraging the OPTE system, we achieved single\u2010step glycoengineering of natural killer (NK)\u201092MI cells with tailored Siglec\u20102 or Siglec\u20103 ligands, which exhibited potent cytotoxicity against B\u2010cell lymphoma (Siglec\u20102\n                    <jats:sup>+<\/jats:sup>\n                    ) and acute myeloid leukemia (Siglec\u20103\n                    <jats:sup>+<\/jats:sup>\n                    ) models. These engineered NK cells displayed significantly enhanced tumor killing capacity, mediated by enhanced granzyme release and cytokine production while maintaining excellent cell viability. This modular platform addresses critical limitations in enzymatic synthesis of modified sialosides and their efficient display on therapeutic cells. Our work establishes a versatile and practical platform for developing next\u2010generation immunotherapies that precisely target the Sia\u2010Siglec axis with improved specificity and functionality.\n                  <\/jats:p>","DOI":"10.1002\/advs.202522474","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T11:13:50Z","timestamp":1772968430000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["One\u2010Step Glycoengineering of NK Cells With High\u2010Affinity Siglec Ligands for Cancer Immunotherapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Shuai","family":"Hu","sequence":"first","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University  Shanghai 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Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruicheng","family":"Qi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyao","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin\u2010Tai","family":"Da","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Biomedicine (Ministry of Education) Shanghai Center for Systems Biomedicine Shanghai Jiao Tong University  Shanghai 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