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ST6GAL1 Glycoengineering Rewires Cytokine Signaling and Preserves Metabolic Fitness in CAR-T Cells Under

Lee Seng Lau1, Maria Suarez1, Aizada Berdalinova1

  • 1Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA.

International Journal of Molecular Sciences
|July 28, 2026
PubMed

Insights

Chimeric antigen receptor (CAR)-T cell therapy faces challenges from the tumor microenvironment. Glycoengineering CAR-T cells with ST6GAL1 enhances their metabolic fitness and resilience against Galectin-3-induced immunosuppression.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Chimeric antigen receptor (CAR)-T cell therapy shows promise for hematologic cancers but is limited by immunosuppression within the tumor microenvironment (TME).
  • Galectin-3 (Gal-3), prevalent in the TME, impairs CAR-T cell function by reducing cytotoxicity and promoting apoptosis.
  • Previous work showed ST6GAL1 expression mitigates Gal-3 binding and improves CAR-T cell function, but the underlying mechanisms were unclear.

Purpose of the Study:

  • To elucidate the mechanistic basis by which ST6GAL1 protects CAR-T cells from Galectin-3-mediated dysfunction.
  • To investigate the metabolic and signaling alterations induced by Gal-3 in CAR-T cells and the protective effects of ST6GAL1.

Main Methods:

  • Assessed metabolic parameters (mitochondrial function, ATP production, glucose utilization) in CAR-T cells exposed to Gal-3, with and without ST6GAL1 overexpression.
  • Analyzed cytokine signaling pathways, including IL-5, STAT5, SOCS1, and SOCS3 expression.
  • Performed transcriptomic analysis on CAR-T cells from diffuse large B-cell lymphoma patients.

Main Results:

  • Galectin-3 induced a hypometabolic state in CAR-T cells, characterized by reduced mitochondrial function and ATP production.
  • ST6GAL1-overexpressing CAR-T cells maintained metabolic fitness and functional resilience under Gal-3 stress.
  • Gal-3 dysregulated cytokine signaling by increasing IL-5 and altering downstream pathways, while ST6GAL1 expression led to increased SOCS1/SOCS3 and attenuated STAT5 activation.
  • Transcriptomic data from lymphoma patients revealed STAT5 signaling and SOCS1 enrichment in complete responders.

Conclusions:

  • Galectin-3 impairs CAR-T cell function by inducing metabolic dysfunction and altering cytokine signaling.
  • ST6GAL1-mediated glycoengineering enhances CAR-T cell metabolic resilience and preserves function under Gal-3-induced immunosuppression.
  • Targeting glycoengineering offers a promising strategy to overcome TME-mediated immunosuppression and improve CAR-T cell therapy efficacy.
Keywords:
CAR-T cellGal-3JAK/STAT signalingSOCS1ST6GAL1glycoengineeringmetabolismtumor microenvironment

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