BACKGROUND: Long non-coding RNAs and N6-methyladenosine RNA methylation represent two pivotal layers of gene regulation. Their extensive crosstalk forms a sophisticated bidirectional network that is fundamentally rewired in cancer. MAIN BODY: This review synthesizes current knowledge to elucidate the principles and consequences of this synergistic axis. We detail how m6A modification dictates long non-coding RNA stability, splicing, localization, and function through recruitment of distinct "reader" proteins, with one "reader" family primarily mediating decay while another promotes stabilization. Conversely, we examine how long non-coding RNAs act as scaffolds, guides, and decoys to modulate the activity and specificity of the m6A machinery, establishing powerful feedforward and feedback loops. This reciprocal regulation converges on multiple cancer hallmarks, including proliferation, metabolic reprogramming, immune evasion, stemness, and therapeutic resistance. We critically discuss experimental strategies to establish causal relationships, including site-directed mutagenesis, CRISPR-based editing, and rescue assays. We also evaluate current methodological limitations in m6A detection, from antibody-dependent approaches to emerging nanopore sequencing, and highlight how single-cell and spatial transcriptomic technologies can resolve cell-state-specific networks within the tumor microenvironment. From a translational perspective, we compare small molecule inhibitors targeting m6A "writers" with RNA-based therapies, addressing their respective delivery challenges and toxicity concerns. Finally, we outline how m6A-related long non-coding RNA signatures serve as prognostic biomarkers and liquid biopsy tools for non-invasive cancer monitoring. CONCLUSION: By integrating molecular mechanisms with clinical perspectives, this review charts a roadmap for targeting the epitranscriptomic-long non-coding RNA circuit in precision oncology.
Wang et al. (Fri,) studied this question.