Glycoengineering CAR-T cells to overcome galectin-3-mediated immunosuppression
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has transformed treatment for relapsed or refractory B-cell malignancies; however, limited in vivo persistence and treatment-limiting toxicities continue to constrain durable efficacy. Because T cell glycan signatures and related galectin-binding properties impact their effector function, we postulated that CAR-T cells similarly displayed signature glycan features that govern their vulnerability to immunosuppressive galectins. In this report, public data mining, galectin-binding and glycosyltransferase expression assessments and glycomics showed that galectin (Gal)-3 was elevated in lymphoma-associated microenvironments and that anti-CD19 CAR-T cells displayed abundant Gal-3-binding glycans, reduced expression of the Gal-3–inhibitory enzyme α2,6-sialyltransferase 1 (ST6GAL1), and heightened susceptibility to Gal-3–mediated immunoregulation. To further explore this association, we enforced ST6GAL1 expression in anti-CD19 CAR-T cells and found that Gal-3-binding was obstructed and Gal-3-mediated cell death and IL-5-induction were reversed. Enforcing ST6GAL1 in CAR-T cells did not weaken tumoricidal activity and significantly improved anti-tumor responses and in vivo persistence. Collectively, this study identifies Gal-3 as a key extrinsic suppressor of CAR-T cell function and establish targeted cell surface α2,6 sialylation as a strategy to enhance CAR-T cell resistance to galectin-rich immunosuppressive microenvironments.
Date Issued
2026-02-18
Date Acceptance
2026-02-02
Citation
Frontiers in Immunology, 2026, 17
ISSN
1664-3224
Publisher
Frontiers Media S.A.
Start Page
1766555
Journal / Book Title
Frontiers in Immunology
Volume
17
Copyright Statement
© 2026 Lau, Suarez, Fernandez, Souchak, Antonopoulos, Hu, Abreu, Koehne, Dell, Haslam, Posey and Dimitroff. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41789075
Subjects
CAR-T cells
cancer glycobiology
cancer immunotherapy
galectins
sialylation modification
Humans
Galectin 3
Sialyltransferases
Animals
beta-D-Galactoside alpha 2-6-Sialyltransferase
Immunotherapy, Adoptive
Receptors, Chimeric Antigen
Immune Tolerance
Antigens, CD
Tumor Microenvironment
Mice
Cell Line, Tumor
T-Lymphocytes
Publication Status
Published
Coverage Spatial
Switzerland
Article Number
1766555
Date Publish Online
2026-02-18