biostudies-literatureTejero JDU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)NIA NIH HHSU.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHS105-114https://www.ebi.ac.uk/biostudies/studies/S-EPMC12904991biostudies-literatureUnknown44(2)Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8⁺ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8⁺ T cell immunity. Treatment of primary CD8⁺ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming anOncogeneMethylmalonic acid induces metabolic abnormalities and exhaustion in CD8<sup>+</sup> T cells to suppress anti-tumor immunity.PMC12904991T32 CA233399R21 AG083720R01 CA279023R00CA218686P30 CA006516P30CA006516R00 CA218686P01CA250984P01 CA250984P30CA076292P30 CA076292P01 CA120964Drapela SRaizada DLazure FTejero JDLiu MIlter DAvram DFendt SMKashfi HCleveland JLHesterberg RSSilvane LFernandez-Garcia JAsara JMGomes APfalseMethylmalonic acid induces metabolic abnormalities and exhaustion in CD8<sup>+</sup> T cells to suppress anti-tumor immunity.Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8⁺ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8⁺ T cell immunity. Treatment of primary CD8⁺ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming an2025-01-01T00:00:00Z2025 Jan2026-07-15T21:26:57.453Z2026-07-09T10:14:02.912ZS-EPMC129049913947249710.1038/s41388-024-03191-1