Acetoacetate suppresses colon cancer via an MR1-MAIT axis

Clay, S. L.; El Tekle, G.; Rashan, E. H.; Fonseca-Pereira, D.; Shin, Y.-H.; Andreeva, N.; Nakatsu, G.; Lobo, A. F.; Chen, S. P.; Bae, S.; Michaud, M.; Glickman, J. N.; Clardy, J.; Vander Heiden, M.; Garrett, W.

doi:10.1101/2025.10.29.685375

bioRxiv · 10.1101/2025.10.29.685375

Acetoacetate suppresses colon cancer via an MR1-MAIT axis

Clay, S. L.·El Tekle, G.·Rashan, E. H.·Fonseca-Pereira, D.·Shin, Y.-H.·Andreeva, N.·Nakatsu, G.·Lobo, A. F.·Chen, S. P.·Bae, S.·Michaud, M.·Glickman, J. N.·Clardy, J.·Vander Heiden, M.·Garrett, W.

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Abstract

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, {beta}-hydroxybutyrate ({beta}HB) or acetoacetate (AcAc), offer an alternative approach. While {beta}HB 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.

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Clay, S. L., El Tekle, G., Rashan, E. H., Fonseca-Pereira, D., Shin, Y.-H., Andreeva, N., Nakatsu, G., Lobo, A. F., Chen, S. P., Bae, S., Michaud, M., Glickman, J. N., Clardy, J., Vander Heiden, M., Garrett, W.. 2025-10-30. Acetoacetate suppresses colon cancer via an MR1-MAIT axis. https://doi.org/10.1101/2025.10.29.685375

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