Front Cell Dev Biol. 2026 ;14
1890102
Epithelial-mesenchymal transition (EMT) is a flexible cell-state program that supports tumor invasion, metastasis, immune escape, and therapy resistance. It is not a simple switch from an epithelial to a mesenchymal phenotype. Instead, cancer cells often move through intermediate or partial EMT states, which allow them to retain cell-cell adhesion while gaining motility and stress tolerance. Recent studies show that RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), A-to-I RNA editing, pseudouridine (Ψ), N4-acetylcytidine (ac4C), and N7-methylguanosine (m7G), add an important post-transcriptional layer to EMT regulation. These modifications control RNA stability, translation, splicing, export, and innate immune sensing. They therefore connect environmental cues, such as hypoxia, TGF-β signaling, inflammatory cytokines, and therapeutic stress, to EMT-related gene expression programs. This review summarizes how major RNA modification systems regulate EMT in cancer. Rather than listing individual findings, we compare common regulatory patterns across tumor types. m6A has the strongest evidence base and acts through writer-reader-eraser modules that regulate EMT transcription factors and signaling pathways such as TGF-β/SMAD, Wnt/β-catenin, PI3K/AKT, EGFR/STAT3, and Notch. m5C and ac4C mainly promote EMT by stabilizing transcripts and enhancing translation, whereas m7G influences EMT through translational reprogramming and codon-biased protein synthesis. A-to-I editing has more complex effects because it can either support immune evasion and plasticity or generate tumor-suppressive RNA isoforms. Ψ-related mechanisms remain less developed, but early evidence suggests roles in RNA stability, stress adaptation, and invasive behavior. We also discuss how EMT and RNA modifications interact with the tumor microenvironment, especially immune suppression and checkpoint resistance. Finally, we evaluate therapeutic opportunities and key challenges. Current studies are limited by reliance on bulk assays, incomplete site-specific validation, weak causal evidence, and insufficient clinical standardization. Future work should integrate single-cell and spatial epitranscriptomics, functional RNA editing tools, and clinical cohorts to define which RNA modification events are true drivers of EMT and which are only associated markers.
Keywords: EMT; HIF-1α; RNA modification; cancer invasion; cell migration; epitranscriptomics; hypoxia; immune evasion