One-carbon metabolism sustains effector T cell function through cell-surface glycosylation
- 1Department of Pathology, Boston Children's Hospital, Boston, MA, USA
Abstract
Folate is a driver of one-carbon metabolism that is essential in T cells. The cellular consequences of its deprivation in CD8+ T cells and impact on anti-tumor function are unknown. Single cell RNA-seq analysis of primary central nervous system lymphoma (PCNSL) patients' tumor samples revealed exhaustion in T cells with high folate metabolism gene expression signature. Functional genomics, metabolite profiling, and glycomics identified disrupted cell surface glycosylation as a major consequence of folate deprivation in CD8+ T cells. Mechanistically, folate deprivation reduced nucleotide sugar levels, perturbed glycosylation, and triggered the apoptotic unfolded protein response. Overexpressing folate transporters in adoptively transferred CD8+ T cells increased intratumoral T cell numbers and reduced exhaustion. Therefore, our data draw a mechanistic line between one-carbon metabolism, cell-surface glycosylation, and anti-tumor T cell function, and support a hypothesis that increased folate uptake can enhance CD8+ T cell function including ex vivo and in vivo CAR-T cells.
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BibTeX
@misc{wang2026onecarbon,
title = {{One-carbon metabolism sustains effector T cell function through cell-surface glycosylation}},
author = {P. Wang and A. Yu and M. Mutaher and A. S. Eisele and S. Mouche and K. Hung and R. Larson and M. Gish and M. Zimmer and J. R. Brook and M. McNerney and L. Hammer and A. Garg and E. Ozeri and A. Y. Wong and B. Petrova and M. Weitman and R. C. Sun and M. Schwartz and J. Tamburini and M. Wenes and N. Hacohen and N. Kanarek},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.756889},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.756889v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - One-carbon metabolism sustains effector T cell function through cell-surface glycosylation
AU - P. Wang
AU - A. Yu
AU - M. Mutaher
AU - A. S. Eisele
AU - S. Mouche
AU - K. Hung
AU - R. Larson
AU - M. Gish
AU - M. Zimmer
AU - J. R. Brook
AU - M. McNerney
AU - L. Hammer
AU - A. Garg
AU - E. Ozeri
AU - A. Y. Wong
AU - B. Petrova
AU - M. Weitman
AU - R. C. Sun
AU - M. Schwartz
AU - J. Tamburini
AU - M. Wenes
AU - N. Hacohen
AU - N. Kanarek
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.756889
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.756889v1
AB - Folate is a driver of one-carbon metabolism that is essential in T cells. The cellular consequences of its deprivation in CD8+ T cells and impact on anti-tumor function are unknown. Single cell RNA-seq analysis of primary central nervous system lymphoma (PCNSL) patients' tumor samples revealed exhaustion in T cells with high folate metabolism gene expression signature. Functional genomics, metabolite profiling, and glycomics identified disrupted cell surface glycosylation as a major consequence of folate deprivation in CD8+ T cells. Mechanistically, folate deprivation reduced nucleotide sugar levels, perturbed glycosylation, and triggered the apoptotic unfolded protein response. Overexpressing folate transporters in adoptively transferred CD8+ T cells increased intratumoral T cell numbers and reduced exhaustion. Therefore, our data draw a mechanistic line between one-carbon metabolism, cell-surface glycosylation, and anti-tumor T cell function, and support a hypothesis that increased folate uptake can enhance CD8+ T cell function including ex vivo and in vivo CAR-T cells.
ER -