Orchestration of immunoregulatory signaling ligand and receptor dynamics by mRNA modifications: Implications for...

RNA modifications are pivotal regulators of gene expression, significantly influencing immune responses by modulating the stability and translation of mRNAs encoding key immunoregulatory ligands and receptors. Among these modifications, N⁶-methyladenosine (m⁶A) is the most abundant and well-characterized, orchestrating immune evasion, T-cell exhaustion, and cytokine production by dynamically regulating transcripts such as PD-L1, IFN-γ, and TGF-β. These modifications critically impact the function and availability of proteins essential for maintaining immune homeostasis and shaping adaptive immune responses. This review comprehensively examines established and emerging roles of mRNA modifications in regulating immunoregulatory signaling, including co-inhibitory and co-stimulatory molecules, chemokines, cytokines, and transforming growth factor-β. We highlight how m6A writers, erasers, and readers finely regulate immune checkpoints and inflammatory pathways across cancer, infection, and autoimmune diseases. Furthermore, the review provides a critical analysis of current discrepancies in the field, emphasizing factors contributing to inconsistencies and offering insights into the complex nature of epigenetic regulation. Challenges and limitations in this rapidly evolving area are also discussed. Advancing detection technologies and developing specific inhibitors targeting RNA-modifying proteins will be crucial for precisely modulating immune responses, paving the way for innovations in precision medicine and immunotherapy.