<p>RNA modifications have emerged as an important regulatory layer that influences gene expression beyond conventional genetic and epigenetic mechanisms. Among the various epitranscriptomic modifications, N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine (Ψ) have been extensively investigated for their roles in RNA stability, splicing, translation, immune regulation, and metabolic homeostasis. Increasing evidence suggests that dysregulation of these modifications contributes to cancer progression, immune evasion, therapeutic resistance, and metabolic disorders, suggesting their potential as therapeutic targets. This review summarizes recent advances in endogenous epitranscriptomic RNA modifications and discusses their relevance in cancer immunotherapy and metabolic diseases. In addition, emerging therapeutic approaches targeting RNA-modifying enzymes, including writers, erasers, and readers, are discussed along with the development of antisense oligonucleotides, RNA-based therapeutics, and delivery systems. Recent progress in lipid nanoparticles, polymeric carriers, and targeted delivery platforms has improved the stability, specificity, and translational potential of RNA-targeted therapies. The review also highlights current challenges associated with clinical translation, including delivery efficiency, therapeutic specificity, and patient heterogeneity. Overall, epitranscriptomic RNA modifications may provide new opportunities for the development of precision therapeutic strategies for cancer and metabolic diseases.</p> Graphical Abstract <p></p>