The Crosstalk Between Metabolic Reprogramming and Histone Methylation in Tumor Immunity and Immunotherapy

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, α-ketoglutarate(α-KG) supports JmjC-domain demethylases, and D-2-hydroxyglutarate (D-2HG) can inhibit α-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–SUZ12/PRC2–H3K27me3 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 α-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.