Yumna A. Butt, Nordin D. Zandhuis, Iosifina P. Foskolou
RNA modifications, particularly m6A, regulate RNA metabolism pathways including splicing, nuclear export, stability, and translation, which are important for T cell function due to their dynamic gene expression needs. m6A modification affects T cell homeostasis, differentiation, and function through writers, erasers, and readers, and is linked to anti-tumor T cell responses. Pharmacological modulation of m6A regulators shows potential in augmenting the efficacy of existing immune therapies.
RNA modifications act as crucial post-transcriptional regulators that fine-tune gene expression to modulate cell function. Among these, N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotic cells, regulating several RNA metabolism pathways including RNA splicing, nuclear export, stability, and translation. These processes are particularly important in rapidly responding immune cells such as T cells, which require dynamic changes in gene expression to support differentiation and effector function. This review focuses on the interplay between immunity and epitranscriptomics and explores the direct and indirect effects of m6A modification on T cells. Specifically, we discuss the role of different writers, erasers, and readers in modulating CD4+ and CD8+ T cell homeostasis, differentiation, and function. In addition, we summarize current evidence linking m6A regulators to anti-tumor T cell responses. Finally, we discuss the recent advances in the field of m6A and immunotherapy by highlighting the potential of pharmacological modulation of m6A regulators in augmenting the efficacy of existing immune therapies. Collectively, by integrating emerging mechanistic and translational insights, this review highlights the pivotal role of m6A regulation in T cell biology and underscores its potential to optimize next-generation immunotherapies.