{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T02:00:33Z","timestamp":1768528833308,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,30]]},"group-title":"Immunology","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Cancer Grand Challenges","award":["C51981-A29063"],"award-info":[{"award-number":["C51981-A29063"]}]},{"name":"Ruth L. Kirschstein NRSA","award":["T32CA207201"],"award-info":[{"award-number":["T32CA207201"]}]},{"name":"NCI","award":["R35CA242379"],"award-info":[{"award-number":["R35CA242379"]}]},{"name":"NCI","award":["P30CA014051"],"award-info":[{"award-number":["P30CA014051"]}]},{"name":"MIT Center for Precision Cancer Medicine"},{"DOI":"10.13039\/100015991","name":"Ludwig Center at MIT","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015991","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Colorectal cancer (CRC) is a leading cause of cancer mortality and additional preventative, and therapeutic strategies are urgently needed. Ketogenic diets have mixed effects on tumorigenesis and compliance is challenging. Exogenous ketones, \u03b2-hydroxybutyrate (\u03b2HB) or acetoacetate (AcAc), offer an alternative approach. While \u03b2HB has been investigated, the anti-cancer effects of AcAc are poorly defined. Here, we show that orally administering ethyl AcAc (EAA) suppresses tumor growth in several pre-clinical CRC models. Single-cell RNA sequencing, flow cytometry, and genetic and antibody-mediated depletion studies reveal that EAA selectively expands and activates cytotoxic mucosal-associated invariant T (MAIT) cells in an MHC class I-related protein 1 (MR1)-dependent manner. EAA increases MR1 expression by tumor monocytes, which is recapitulated in human cell cultures, where AcAc and 5-amino-6-D-ribitylaminouracil (5-A-RU) induce MAIT cell expansion and tumor killing. Mechanistically, AcAc converts to methylglyoxal, combining with microbially-derived 5-A-RU to generate 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a potent MR1 ligand. These findings identify an AcAc-MR1-MAIT cell axis as a potential immunotherapy approach for CRC therapy.<\/jats:p>","DOI":"10.1101\/2025.10.29.685375","type":"posted-content","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T01:05:27Z","timestamp":1761872727000},"source":"Crossref","is-referenced-by-count":0,"title":["Acetoacetate suppresses colon cancer via an MR1-MAIT axis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1966-892X","authenticated-orcid":false,"given":"Slater L.","family":"Clay","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geniver","family":"El Tekle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edrees H.","family":"Rashan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diogo","family":"Fonseca-Pereira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yern-Hyerk","family":"Shin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Andreeva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geicho","family":"Nakatsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayesha F.","family":"Lobo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sway P.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sena","family":"Bae","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monia","family":"Michaud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan N.","family":"Glickman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon","family":"Clardy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6702-4192","authenticated-orcid":false,"given":"Matthew G.","family":"Vander Heiden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5092-0150","authenticated-orcid":false,"given":"Wendy S.","family":"Garrett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025110406450900000_2025.10.29.685375v2.1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2022-327736"},{"key":"2025110406450900000_2025.10.29.685375v2.2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21772"},{"key":"2025110406450900000_2025.10.29.685375v2.3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.0106"},{"key":"2025110406450900000_2025.10.29.685375v2.4","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14071732"},{"key":"2025110406450900000_2025.10.29.685375v2.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04649-6"},{"key":"2025110406450900000_2025.10.29.685375v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56678-0"},{"key":"2025110406450900000_2025.10.29.685375v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.04.027"},{"key":"2025110406450900000_2025.10.29.685375v2.8","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.cmet.2016.12.010","article-title":"Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth","volume":"25","year":"2017","journal-title":"Cell Metabolism"},{"key":"2025110406450900000_2025.10.29.685375v2.9","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1007\/s10238-021-00710-2","article-title":"The use of ketogenic diets in cancer patients: a systematic review","volume":"21","year":"2021","journal-title":"Clin Exp Med"},{"key":"2025110406450900000_2025.10.29.685375v2.10","doi-asserted-by":"crossref","first-page":"702802","DOI":"10.3389\/fnut.2021.702802","article-title":"Ketogenic Diets and Chronic Disease: Weighing the Benefits Against the Risks","volume":"8","year":"2021","journal-title":"Front Nutr"},{"key":"2025110406450900000_2025.10.29.685375v2.11","doi-asserted-by":"crossref","first-page":"eadx2752","DOI":"10.1126\/sciadv.adx2752","article-title":"A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice","volume":"11","year":"2025","journal-title":"Sci. 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