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Regulatory T cells (Tregs) exhibit unique metabolic adaptability to this lactate-rich environment, yet the underlying mechanisms remain incompletely understood. Here, we demonstrate that the monocarboxylate transporter MCT4 is upregulated in tumor-infiltrating Tregs and mediates direct lactate uptake. Using Treg-specific conditional knockout (cKO) mice, we show that MCT4 deficiency does not affect basal Treg development but abrogates lactate-induced Foxp3 stabilization and impairs Treg suppressive function. Mechanistically, MCT4-mediated lactate uptake promotes the lactylation of Foxp3 at lysine 277 (K277), which competitively inhibits its ubiquitination, thereby enhancing Foxp3 protein stability and nuclear localization. Nuclear Foxp3 subsequently interacts with IRF3 to promote IL-10 transcription and secretion. In the B16 melanoma model, MCT4-deficient Tregs display compromised stability and reduced tumor infiltration, leading to enhanced CD8+ T cell effector function and attenuated tumor growth. Collectively, our findings reveal that MCT4-mediated lactate uptake sustains Treg stability and function through Foxp3 lactylation, identifying MCT4 as a potential therapeutic target for modulating Treg activity in cancer.<\/jats:p>","DOI":"10.3390\/ijms27104619","type":"journal-article","created":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T12:06:07Z","timestamp":1779365167000},"page":"4619","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Lactate Uptake by MCT4 Facilitates Stability and Suppressive Function of Tumor-Infiltrating Regulatory T Cells by Promoting Foxp3 Lactylation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3385-6449","authenticated-orcid":false,"given":"Zhaofei","family":"Wu","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, Department of Immunology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Liu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, Department of Immunology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Xian","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Medical Immunology, Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Wang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, Department of Immunology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, Department of Immunology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunliang","family":"Qi","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, Department of Immunology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, Department of Immunology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-Related Diseases, Department of Immunology, School of Basic Medical Sciences, Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","article-title":"Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). 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