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Malignant pleural effusion (MPE) from humans and mouse was used to investigate the potential mechanisms by which lactate regulates TNFR2 expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Treg cells with high TNFR2 expression exhibited elevated levels of immune checkpoint molecules. Additionally, the high expression of TNFR2 on Treg cells was positively correlated with a poor prognosis in MPE patients. Moreover, we revealed that lactate upregulated TNFR2 expression on Treg cells, thereby enhancing their immunosuppressive function in MPE. Mechanistically, lactate modulated the gene transcription of transcription factor nuclear factor-\u03baB p65 (NF-\u03baB p65) through histone H3K18 lactylation (H3K18la), subsequently upregulating the gene expression of TNFR2 and expediting the progression of MPE. Notably, lactate metabolism blockade combined with immune checkpoint blockade (ICB) therapy effectively enhanced the efficacy of ICB therapy, prolonged the survival time of MPE mice, and improved immunosuppression in the microenvironment of MPE.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The study explains the mechanism that regulates TNFR2 expression on Treg cells and its function in MPE progression, providing novel insights into the epigenetic regulation of tumor development and metabolic strategies for MPE treatment by targeting lactate metabolism in Treg cells.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2024-010040","type":"journal-article","created":{"date-parts":[[2024,12,25]],"date-time":"2024-12-25T20:30:17Z","timestamp":1735158617000},"page":"e010040","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":59,"title":["Lactylation-driven TNFR2 expression in regulatory T cells promotes the progression of malignant pleural effusion"],"prefix":"10.1136","volume":"12","author":[{"given":"Qianqian","family":"Xue","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7671-4339","authenticated-orcid":false,"given":"Wenbei","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoshan","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Xiang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haolei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3120-3017","authenticated-orcid":false,"given":"Qiong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Huazhong University of Science and Technology, Wuhan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,12,25]]},"reference":[{"key":"2025100311060255000_12.12.e010040.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0175-7"},{"key":"2025100311060255000_12.12.e010040.2","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-14-0095"},{"key":"2025100311060255000_12.12.e010040.3","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13081850","article-title":"Recruitment and Expansion of Tregs Cells in the Tumor Environment-How to Target Them?","volume":"13","author":"Cinier","year":"2021","journal-title":"Cancers (Basel)"},{"key":"2025100311060255000_12.12.e010040.4","doi-asserted-by":"crossref","first-page":"101476","DOI":"10.1016\/j.smim.2021.101476","article-title":"Tumor resident regulatory T cells","volume":"52","author":"Glasner","year":"2021","journal-title":"Semin Immunol"},{"key":"2025100311060255000_12.12.e010040.5","doi-asserted-by":"crossref","unstructured":"Yi M , Zhang J , Li A , et al . 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