N⁶-Methyladenosine: an RNA modification as a central regulator of cancer.

Abstract

N⁶-Methyladenosine (m⁶A) is a modified nucleotide in mRNAs and non-coding RNAs that influences gene expression, primarily by promoting the degradation of specific transcripts. Recent studies have highlighted the dynamic and context-dependent roles of this RNA modification in cancer, implicating it in tumorigenesis, immune evasion and therapeutic resistance. In this Review, we discuss the functional roles of m⁶A writers, erasers and readers in cancer. We highlight how m⁶A dysregulation contributes to oncogenic processes, including cell differentiation and immune microenvironment remodelling. Using haematological malignancies as an example, we highlight the principles of m⁶A-dependent regulation that may be broadly relevant across cancer types. Notably, inhibitors targeting the m⁶A writer methyltransferase-like 3 (METTL3) have emerged as potential cancer therapeutics. METTL3 inhibitors not only disrupt m⁶A-dependent pathways but also elevate double-stranded RNA levels, activating innate immune responses and antitumour immunity. We emphasize the need for high-resolution quantitative m⁶A mapping in cancer and mechanistic studies to better understand the specific transcripts that exhibit altered patterns of m⁶A in cancer and to identify patient subgroups most likely to benefit from METTL3 inhibitors.