{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:38:03Z","timestamp":1790048283085,"version":"4.0.1"},"posted":{"date-parts":[[2023,11,3]]},"group-title":"Immunology","reference-count":57,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,11,3]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  Nucleotides perform important metabolic functions, carrying energy and feeding nucleic acid synthesis. Here, we use isotope tracing-mass spectrometry to quantitate the contributions to purine nucleotides of salvage versus\n                  <jats:italic>de novo<\/jats:italic>\n                  synthesis. We further explore the impact of augmenting a key precursor for purine synthesis, one-carbon (1C) units. We show that tumors and tumor-infiltrating T cells (relative to splenic T cells) synthesize purines\n                  <jats:italic>de novo<\/jats:italic>\n                  . Purine synthesis requires two 1C units, which come from serine catabolism and circulating formate. Shortage of 1C units is a potential bottleneck for anti-tumor immunity. Elevating circulating formate drives its usage by tumor-infiltrating T cells. Orally administered methanol functions as a formate pro-drug, with deuteration enabling control of formate-production kinetics. In MC38 tumors, safe doses of methanol raise formate levels and augment anti-PD-1 checkpoint blockade, tripling durable regressions. Thus, 1C deficiency can gate antitumor immunity and this metabolic checkpoint can be overcome with pharmacological 1C supplementation.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Statement of significance<\/jats:title>\n                  <jats:p>Checkpoint blockade has revolutionized cancer therapy. Durable tumor control, however, is achieved in only a minority of patients. We show that the efficacy of anti-PD-1 blockade can be enhanced by metabolic supplementation with one-carbon donors. Such donors support nucleotide synthesis in tumor-infiltrating T cells and merit future clinical evaluation.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.11.01.565193","type":"posted-content","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T22:30:12Z","timestamp":1699050612000},"source":"Crossref","is-referenced-by-count":5,"title":["One-carbon unit supplementation fuels tumor-infiltrating T cells and augments checkpoint blockade"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1062-2092","authenticated-orcid":false,"given":"Xincheng","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1554-1649","authenticated-orcid":false,"given":"Zihong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2147-6003","authenticated-orcid":false,"given":"Caroline R.","family":"Bartman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Xing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kellen","family":"Olszewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1247-4727","authenticated-orcid":false,"given":"Joshua D.","family":"Rabinowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023110803101186000_2023.11.01.565193v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160809"},{"key":"2023110803101186000_2023.11.01.565193v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.12.006"},{"key":"2023110803101186000_2023.11.01.565193v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.10.040"},{"key":"2023110803101186000_2023.11.01.565193v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0048-x"},{"key":"2023110803101186000_2023.11.01.565193v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nature12138"},{"key":"2023110803101186000_2023.11.01.565193v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4256"},{"key":"2023110803101186000_2023.11.01.565193v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00541-y"},{"key":"2023110803101186000_2023.11.01.565193v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.016"},{"key":"2023110803101186000_2023.11.01.565193v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.012"},{"key":"2023110803101186000_2023.11.01.565193v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03442-1"},{"key":"2023110803101186000_2023.11.01.565193v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.09.031"},{"key":"2023110803101186000_2023.11.01.565193v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2682-1"},{"key":"2023110803101186000_2023.11.01.565193v1.13","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-16-0103"},{"key":"2023110803101186000_2023.11.01.565193v1.14","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.124989"},{"key":"2023110803101186000_2023.11.01.565193v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108500"},{"key":"2023110803101186000_2023.11.01.565193v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/nature10491"},{"key":"2023110803101186000_2023.11.01.565193v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30274-8"},{"key":"2023110803101186000_2023.11.01.565193v1.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM194806032382301"},{"key":"2023110803101186000_2023.11.01.565193v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.08.009"},{"key":"2023110803101186000_2023.11.01.565193v1.20","doi-asserted-by":"crossref","unstructured":"Kamatani, N. ; Jinnah, H.A. ; Hennekam, R.C.M. ; van Kuilenburg, A.B.P. 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