{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:48:45Z","timestamp":1791953325858,"version":"4.3.4"},"reference-count":179,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82403344"],"award-info":[{"award-number":["82403344"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82403344"],"award-info":[{"award-number":["82403344"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2023QH453"],"award-info":[{"award-number":["ZR2023QH453"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Histone methylation regulates chromatin structure and gene expression, whereas tumor metabolism provides bioenergetic and biosynthetic inputs. These processes are bidirectionally linked: S-adenosylmethionine supplies methyl groups for histone methyltransferases, \u03b1-ketoglutarate(\u03b1-KG) supports JmjC-domain demethylases, and D-2-hydroxyglutarate (D-2HG) can inhibit \u03b1-KG-dependent dioxygenases. Conversely, histone methylation can regulate metabolic gene expression, as illustrated by KMT2D-dependent enhancer remodeling and glycolytic gene expression in melanoma models. Lactate regulates chromatin through histone lactylation, a modification distinct from histone methylation; where the two intersect, as in the retinoblastoma H3K18la\u2013SUZ12\/PRC2\u2013H3K27me3 circuit, the crosstalk is model-specific. This review examines these interactions in tumor cells and the immune microenvironment, emphasizing enzyme specificity, histone mark, cell type and experimental context. We highlight that changes in S-adenosylmethionine or \u03b1-KG do not produce uniform effects across enzymes, loci or cell states, and that tumor-associated macrophages are not captured by a fixed M1\/M2 metabolic dichotomy. Mechanistic findings, preclinical results and early-phase clinical observations are considered separately; single-arm activity reported for valemetostat in adult T-cell leukemia\/lymphoma is presented as activity in a defined cohort, not as an established survival benefit. Finally, we discuss how single-cell and spatial approaches can help resolve cell-type-specific and niche-specific interactions in heterogeneous tumors.<\/jats:p>","DOI":"10.3390\/cells15191786","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T15:20:59Z","timestamp":1790781659000},"page":"1786","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Crosstalk Between Metabolic Reprogramming and Histone Methylation in Tumor Immunity and Immunotherapy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9270-2479","authenticated-orcid":false,"given":"Jiayao","family":"Dou","sequence":"first","affiliation":[{"name":"Department of Pathology and Pathophysiology, School of Basic Medicine, Shandong Second Medical University, Weifang 261000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruicheng","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Medical Informatics, School of Basic Medicine, Shandong Second Medical University, Weifang 261000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pathology and Pathophysiology, School of Basic Medicine, Shandong Second Medical University, Weifang 261000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Medical Informatics, School of Basic Medicine, Shandong Second Medical University, Weifang 261000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Reed, L., Abraham, J., Patel, S., and Dhar, S.S. 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