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

Peng Wang; Amy Yu; Mohammed Mutaher; Almut S. Eisele; Sarah Mouche; Kaitlyn Hung; Reece Larson; Madeline Gish; Margaret D. Zimmer; Jeannette R. Brook; Miriam McNerney; Lea Hammer; Arjun Garg; Efrat Ozeri; Alan Y. L. Wong; Boryana Petrova; Michal Weitman; Ramon C. Sun; Jérôme Tamburini; Mathias Wenes; Marc A. Schwartz; Nir Hacohen; Naama Kanarek

doi:10.64898/2026.10.06.756889

Cell BiologybioRxivOct 7, 2026

Preprint

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

Peng Wang iD, Amy Yu iD, Mohammed Mutaher iD, Almut S. Eisele iD, Sarah Mouche iD, Kaitlyn Hung iD, Reece Larson iD, Madeline Gish iD, Margaret D. Zimmer iD, Jeannette R. Brook iD, Miriam McNerney iD, Lea Hammer iD, Arjun Garg iD, Efrat Ozeri, Alan Y. L. Wong iD, Boryana Petrova iD, Michal Weitman iD, Ramon C. Sun iD, Jérôme Tamburini iD, Mathias Wenes iD, Marc A. Schwartz iD, Nir Hacohen iD, Naama Kanarek iD

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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