The crosstalk between epigenetics and metabolism in the malignant cell

Metabolic-epigenetic coupling is recognized as a central hallmark of malignant transformation, characterized by dynamic interplay between cellular metabolism and epigenetic regulation. Cancer cells undergo metabolic reprogramming to meet new demands due to increased biosynthesis and shifted bioenergetics. These changes are responsible for the production of metabolites that are used as substrates or cofactors for key enzymes involved in epigenetic regulation. Thereby, the chromatin structure and gene expression suffer critical changes. Epigenetic modifications including DNA methylation, histone acetylation or non-coding RNA activity, are regulating the transcription of metabolic genes, reshaping the tumor metabolic phenotype. The bidirectional crosstalk between epigenetics and metabolism drives key cancer hallmarks such as proliferation, immune evasion, and drug resistance. Recent discoveries in multi-omics, single-cell sequencing and spatial transcriptomics have opened a new era of high-resolution mapping of metabolic and epigenetic alterations, revealing the high heterogeneity in tumor cells and highlight novel therapeutic targets. In this review we aim to summarize the latest approaches in technological advances in integrated metabolomics and epigenomics, to highlight the critical crosstalk between metabolism and epigenetic changes, and to underscore the need of a deep understanding of these interactions for integrating the multi-omics approach in precision oncology.