{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:08:09Z","timestamp":1784542089681,"version":"3.55.0"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"NIH\/NCI","doi-asserted-by":"publisher","award":["R01CA282520"],"award-info":[{"award-number":["R01CA282520"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"FIU\/HWCOM-Baptist Health Pilot Grant"},{"name":"Florida Education Fund McKnight Fellowship"},{"name":"University of Graduate School FIU"},{"name":"Janssen & Janssen Scholars of Oncology Diversity Engagement Program"},{"name":"FIU Presidential Fellowship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable efficacy in hematologic malignancies; however, durable responses remain limited by tumor microenvironment (TME)-mediated immunosuppression. Galectin-3 (Gal-3), a \u03b2-galactoside-binding lectin enriched in the TME, contributes to CAR-T cell dysfunction by impairing cytotoxicity, promoting apoptosis, and altering cellular signaling. While we previously demonstrated that enforced expression of the \u03b12,6 sialyltransferase ST6GAL1 reduces galectin binding and improves CAR-T cell function, the mechanistic basis underlying this protection remains unclear. Here, we report that Gal-3 induced a hypometabolic state in CAR-T cells characterized by reduced mitochondrial function, ATP production, and glucose utilization. In contrast, ST6GAL1-overexpressing CAR-T cells preserved metabolic fitness and functional resilience under Gal-3 stress. Additionally, Gal-3 rewired cytokine signaling by increasing IL-5 expression and dysregulating downstream pathways, whereas enforced ST6GAL1 expressing CAR-T cells exhibited increased SOCS1 and SOCS3 expression and attenuated STAT5 activation. Transcriptomic analysis of CAR-T cells from diffuse large B-cell lymphoma patients further revealed enrichment of STAT5-associated signaling and SOCS1 expression in complete responders compared to partial responders. Collectively, these findings identify glycoengineering as a promising strategy to enhance CAR-T cell persistence and function under Gal-3-mediated immunosuppressive stress.<\/jats:p>","DOI":"10.3390\/ijms27146393","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6393","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ST6GAL1 Glycoengineering Rewires Cytokine Signaling and Preserves Metabolic Fitness in CAR-T Cells Under Galectin-3-Mediated Immunosuppression"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1016-4338","authenticated-orcid":false,"given":"Lee Seng","family":"Lau","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Suarez","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aizada","family":"Berdalinova","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9091-1830","authenticated-orcid":false,"given":"Rebecca Z.","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajib Kumar","family":"Shil","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Souchak","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6606-4371","authenticated-orcid":false,"given":"Kim","family":"Tieu","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8711-629X","authenticated-orcid":false,"suffix":"Jr.","given":"Avery D.","family":"Posey","sequence":"additional","affiliation":[{"name":"Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4224-7621","authenticated-orcid":false,"given":"Charles J.","family":"Dimitroff","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1126\/science.aar6711","article-title":"CAR T cell immunotherapy for human cancer","volume":"359","author":"June","year":"2018","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e948125","DOI":"10.12659\/MSM.948125","article-title":"A Review of CAR T Cells and Adoptive T-Cell Therapies in Lymphoid and Solid Organ Malignancies","volume":"31","author":"Parums","year":"2025","journal-title":"Med. 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