This review critically synthesizes the multifaceted roles of RNA modifications to bridge the gap between descriptive epitranscriptomic mapping and functional tumor biology, and aims to facilitate the translation of epitranscriptomic findings into clinical applications.
Abstract
RNA modifications, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 7-methylguanosine (m7G), pseudouridine (Ψ), and adenosine-to-inosine (A-to-I) editing, constitute a dynamic epitranscriptomic network that profoundly regulates RNA metabolism and gene expression. Their dysregulation is increasingly recognized as a hallmark of cancer. This review critically synthesizes the multifaceted roles of RNA modifications to bridge the gap between descriptive epitranscriptomic mapping and functional tumor biology. We systematically evaluate how writers, readers, and erasers dictate transcript stability and translation efficiency, driving tissue-specific tumor evolution across diverse malignancies. Crucially, we explore the intersection of RNA modifications and the tumor immune microenvironment, detailing their mechanisms in orchestrating immune evasion, altering antigen presentation, and regulating immune checkpoints. Furthermore, we examine how epitranscriptomic reprogramming dictates cellular responses to chemotherapy, radiotherapy, targeted treatments, and immunotherapy. By comprehensively analyzing these mechanisms, this review aims to facilitate the translation of epitranscriptomic findings into clinical applications, laying a theoretical foundation for targeted anti-tumor strategies.
Epitranscriptomic regulation has emerged as a critical mechanism in cancer biology, particularly in the development of chemoresistance. RNA modifications including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), 7-methylguanosine (m7G), pseudouridine (Ψ), and A-to-I editing dynamically control mRNA stability, splicing, translation, and degradation. RNA-modifying proteins called 'writers,' 'erasers,' and 'readers' regulate post-transcriptional networks to enable tumor adaptation and chemoresistance. In platinum-resistant tumors, epitranscriptomic changes modulate DNA damage response, apoptosis, drug efflux, and detoxification pathways. Preclinical studies demonstrate that pharmacological inhibition of key regulators, such as METTL3 inhibitors (STC-15, STM2457, UZH2) or FTO inhibitors, can sensitize tumors to platinum drugs and stimulate anti-tumor immunity. However, clinical translation remains limited by off-target effects, toxicity, and highly context-specific responses. Epitranscriptomic profiling may help identify novel biomarkers and guiding precision strategies to overcome chemoresistance.
P. Harvanik, T. Hudáková, M. Šemeláková et al.· Advances in Medical Sciences· 1 citation
It is argued that while epitranscriptomics represents a compelling regulatory axis in cancer cell death, advancing the field will require integrative, high-resolution, and functionally precise approaches to move beyond correlative frameworks toward mechanistic and clinically actionable insights.
A. Mukherjee, Ankit Kumar Bharti, D. Mathew et al.· Functional & Integrative Gen...· 0 citations
Breast cancer remains a leading cause of cancer-related mortality worldwide, largely due to its molecular heterogeneity and therapeutic resistance. N6-methyladenosine (m6A) RNA modification has recently emerged as a critical epitranscriptomic regulator involved in diverse aspects of RNA metabolism, including stability, splicing, translation, and degradation. Accumulating evidence suggests that dysregulation of m6A modification is associated with breast cancer progression, metastasis, and treatment resistance. In this review, we systematically summarize the functional roles of m6A regulators, including writers, erasers, and readers, in breast cancer biology. We further discuss the involvement of m6A modification in key oncogenic signaling pathways, metabolic reprogramming, and tumor immune microenvironment remodeling. Importantly, we highlight the emerging clinical potential of m6A regulators as diagnostic and prognostic biomarkers, as well as therapeutic targets for overcoming drug resistance. Finally, we outline current challenges and future perspectives, emphasizing the need for integrating multi-omics approaches and developing m6A-targeted therapies to advance precision oncology in breast cancer.
Zilong Chen, Chi Zhou, Zhuo-Run Song et al.· Cancer Treatment and Researc...· 0 citations
Advances provide the first chemical foothold for therapeutic modulation of m7G pathways and underscore METTL1 as a promising yet complex target requiring careful biological stratification.
Emanuele Fabbrizi, Gebremedhin S. Hailu, Andrea Mancini et al.· Journal of Medicinal Chemist...· 0 citations
Altered post-transcriptional regulation contributes to cancer development and treatment resistance. N6-methyladenosine (m6A) modification and noncoding RNAs are closely connected within this process and can regulate one another in both directions. This review summarizes the m6A regulatory system, the biological characteristics of major ncRNA classes, and the mechanisms through which m6A and ncRNAs interact in cancer. m6A can affect ncRNA biogenesis, stability, localization, protein binding, and translation, whereas ncRNAs can alter the expression or activity of m6A writers, erasers, and readers and influence their interactions with specific RNA targets. The effects of these pathways vary with the RNA involved, the modified site, the associated proteins, and the cellular context, which helps explain why similar changes in the m6A machinery can produce different outcomes in different tumors. m6A-ncRNA interactions have been associated with tumor progression, metabolic adaptation, regulated cell death, immune regulation, and response to anticancer treatment. Several ncRNAs involved in these pathways have also been linked to prognosis, recurrence, or treatment response in patient cohorts. Experimental studies have begun to examine therapeutic strategies based on ncRNA inhibition or restoration and, in a smaller number of cases, direct manipulation of defined m6A events. The review also considers the clinical evidence for these pathways and the practical challenges that need to be addressed before they can be more widely explored as biomarkers or therapeutic targets.
Nan Li, Jia-Xue Lu, Wen-Ling Zhang· International Immunopharmaco...· 0 citations
This review focuses on the interplay between immunity and epitranscriptomics and explores the direct and indirect effects of m6A modification on T cells and highlights the pivotal role of m6A regulation in T cell biology and its potential to optimize next-generation immunotherapies.
Yumna A. Butt, Nordin D. Zandhuis, I. Foskolou· Immuno· 0 citations
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