The crosstalk between broad epigenetic modification and T cell metabolism within tumor microenvironment.

T cells play an important role in adaptive immune responses, providing antigen specificity for pathogen and tumor recognition. Recent studies have elucidated the complex interplay between T cell metabolism and broad epigenetic modifications in response to tumors, occurring at transcriptional, post-transcriptional, and post-translational levels. At the transcriptional level, gene expression is regulated through mechanisms such as DNA methylation, chromatin remodeling, and transcription factor activity. Post-transcriptionally, gene expression is further modulated by non-coding RNAs and RNA modifications, an area of increasing research interest. In addition, histone proteins are primarily regulated by well-established post-translational modifications (PTMs), including acetylation and methylation. Novel PTMs such as succinylation, glycosylation, glutamylation, and lactylation add complexity to the regulation and warrant further investigation. At present, the interaction between CD8 T cell metabolism and epigenetic modifications in response to malignancies has been reported extensively. However, the interplay in CD4 T cells remains less understood. In this review, we introduce the differentiation trajectories of T cells and critically evaluate existing interplay between metabolic activity and epigenetic modifications influences the functional dynamics in both CD8 and CD4 T cells, offering promising avenues for the development of novel cancer immunotherapies.