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However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA (\n                    <jats:italic>\n                      Kras\n                      <jats:sup>G12D\/+<\/jats:sup>\n                      Trp53\n                      <jats:sup>R172H\/+<\/jats:sup>\n                      Ad-Cre\n                    <\/jats:italic>\n                    ) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I\u2013deficient tumor cells cocultured with T cells were more susceptible to T cell\u2013mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I\u2013knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2\/Tigit-associated immunosuppression. ST6GalNAc-I\u2013deficient cells exhibited reduced P-DMEA metabolite levels, while administration of P-DMEA promoted LUAD cell proliferation via MUC5AC. MUC5AC interacted and colocalized with PRRC1 in the Golgi, suggesting a potential role for PRRC1 in MUC5AC glycosylation. Mice injected with ST6GalNAc-I\/MUC5AC-deficient cells (human LUAD) exhibited reduced lung tumor incidence, angiogenesis, and liver metastases. Mechanistically, ST6GalNAc-I\/MUC5AC regulates VCAN-V1, a key factor in tumor matrix remodeling during angiogenesis and metastasis. These findings demonstrate that ST6GalNAc-I\u2013mediated sialylation of NECTIN2\/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and\/or metastasis.\n                  <\/jats:p>","DOI":"10.1172\/jci186863","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T14:00:41Z","timestamp":1747231241000},"source":"Crossref","is-referenced-by-count":20,"title":["ST6GalNAc-I regulates tumor cell sialylation via NECTIN2\/MUC5AC-mediated immunosuppression and angiogenesis in non\u2013small cell lung cancer"],"prefix":"10.1172","volume":"135","author":[{"given":"Muthamil Iniyan","family":"Appadurai","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9630-1235","authenticated-orcid":true,"given":"Sanjib","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular 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