The relevance of m⁶A RNA modifications in cancer stem cells

Cancer is a multifactorial disease, driven by dysregulation of cellular processes that are controlled by the complex influence of DNA and RNA-level regulatory mechanisms. Epitranscriptomics has surfaced as a prominent field in cancer research, providing a clearer understanding of post-transcriptional regulation of gene expression. In particular, N⁶-methyladenosine (m⁶A) is the most abundant internal modification in eukaryotic mRNA, and has emerged as a key regulator of post-transcriptional gene expression. Through the coordinated activity of methyltransferases ("writers"), demethylases ("erasers") and binding proteins ("readers"), m⁶A dynamically modulates important RNA processing steps, including translation, stability, decay and splicing. Notably, m⁶A regulatory proteins are implicated in several stemness pathways acting as oncogenic drivers or tumor suppressors in a highly context-dependent manner. This regulatory flexibility is particularly relevant in cancer stem cells (CSCs), a highly plastic subpopulation involved in tumor initiation, progression, metastasis and therapy resistance. Indeed, some of the major challenges in oncology arise from cancer cell adaptability, tumor heterogeneity and microenvironment-dependent outcomes, processes in which m⁶A emerges as a critical regulatory layer. This review summarizes the mechanisms of m⁶A regulation and its biological effects, and provides an overview of the influence of m⁶A in CSC phenotypes. Finally, it explores how m⁶A affects therapeutic responses, future perspectives in oncology and the key challenges currently under investigation in this field.