Year: 2026
Type: preprint
Abstract: Summary Folate is an essential driver of one-carbon metabolism. The cellular consequences of its deprivation in CD8 + T cell 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. Highlights Although folate metabolism genes are highly expressed in both proliferating tumor and CD8 + T cells from primary central nervous system lymphoma patients, the T cells are exhausted while the tumor cells thrive Folate is depleted in the TME of MC38-OVA and B16-OVA tumors Folate deprivation impairs function and proliferation of CD8 + T cells Folate is essential for nucleotide sugar metabolism, and its depletion results in perturbation of cell surface glycosylation Genetic engineering to increase folate uptake by T cells increases intratumoral T cell numbers and reduces exhaustion
Authors: Peng Wang, Amy Yu, Mohammed Mutaher, Almut S. Eisele, Sarah Mouche, Kaitlyn Hung, Reece C. Larson, Madeline Gish, Margaret Zimmer, Jeanette R. Brook, Miriam McNerney, Lea Hammer, Arjun Garg, Efrat Ozeri, Alan Y. L. Wong, Boryana Petrova, Michal Weitman, Ramon C. Sun, Jerome Tamburini, Mathias Wenes, Marc Schwartz, Nir Hacohen, Naama Kanarek
Institutions: Boston Children's Hospital, Harvard University, Broad Institute, Massachusetts Institute of Technology, University of Geneva, Swiss Cancer Center Léman, University of Florida, Technion – Israel Institute of Technology, Medical University of Vienna, University Hospital of Geneva, Massachusetts General Hospital
Language: English
Subfield: Nutrition and Dietetics
Field: Nursing
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Deutscher Akademischer Austauschdienst, Croucher Foundation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Hôpitaux Universitaires de Genève, National Institute on Aging, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Awards: Studien zu ausgewählten Motiven auf Stempelsiegeln aus Palästina., Graduate Research Fellowship Program (GRFP), Aberrant Glycogen Modulates Cerebral Glucose Metabolism in Aging and Alzheimer's Disease, Brain glucose deficiency: mechanisms and modulation, G9000842252, Deciphering the Glycan Code in Human Alzheimer's Disease Brain, Mechanisms Promoting Copper Dependent Cell Death in Cancer, Aberrant Glycogen in Lung Adenocarcinoma Tumorigenesis, Targeting Glycogen Metabolism in Ewing's Sarcoma: Diagnostic, Prognostic, and Therapeutic Applications
OpenAlex ID: W7220864481