One-carbon metabolism sustains effector T cell function through cell-surface glycosylation

Wang, P.; Yu, A.; Mutaher, M.; Eisele, A. S.; Mouche, S.; Hung, K.; Larson, R.; Gish, M.; Zimmer, M.; Brook, J. R.; McNerney, M.; Hammer, L.; Garg, A.; Ozeri, E.; Wong, A. Y.; Petrova, B.; Weitman, M.; Sun, R. C.; Schwartz, M.; Tamburini, J.; Wenes, M.; Hacohen, N.; Kanarek, N.

doi:10.64898/2026.10.06.756889

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bioRxiv · 10.64898/2026.10.06.756889

One-carbon metabolism sustains effector T cell function through cell-surface glycosylation

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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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Wang, P., Yu, A., Mutaher, M., Eisele, A. S., Mouche, S., Hung, K., Larson, R., Gish, M., Zimmer, M., Brook, J. R., McNerney, M., Hammer, L., Garg, A., Ozeri, E., Wong, A. Y., Petrova, B., Weitman, M., Sun, R. C., Schwartz, M., Tamburini, J., Wenes, M., Hacohen, N., Kanarek, N.. 2026-10-07. One-carbon metabolism sustains effector T cell function through cell-surface glycosylation. https://doi.org/10.64898/2026.10.06.756889

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