The review organizes the field around the central concept of writers, erasers and readers. Writer enzymes install modifications on RNA; erasers remove them; and reader proteins recognize the marks and translate them into functional consequences. The best-characterized internal modification is N6-methyladenosine, or m6A, the addition of a methyl group to the sixth nitrogen of adenosine. The core writer complex includes the methyltransferases METTL3 and METTL14 together with accessory factors such as WTAP, VIRMA and METTL16, all drawing their methyl groups from the universal cellular methyl donor S-adenosylmethionine. Removal is handled by two demethylases, FTO and ALKBH5, while recognition is mediated by a family of readers that includes YTHDC1, the YTHDF proteins 1 through 3, and the IGF2BP family of mRNA-binding proteins, as well as HNRNPC and HNRNPA2B1, which respond indirectly to m6A by altering RNA structure. Because each of these components can act on hundreds of different transcripts, a single change in writer or eraser activity can reprogram entire gene-expression networks at once.

Beyond m6A, the review catalogues a growing cast of chemically distinct marks with established roles in cancer. 5-methylcytosine, or m5C, is installed by the NSUN family of methyltransferases and by DNMT2, and is read by proteins such as ALYREF to influence RNA export and stability. N4-acetylcytidine, ac4C, deposited by the acetyltransferase NAT10, enhances mRNA stability and translation efficiency. N1-methyladenosine, m1A, and N7-methylguanosine, m7G, mark transcript start sites and cap structures respectively, with METTL5, ZCCHC4 and TRMT112 among the enzymes implicated in their deposition. Pseudouridine, the most abundant internal RNA modification, is catalyzed by pseudouridine synthases, including the dyskerin complex that also maintains telomeres. Even RNA editing, in which adenosine is converted to inosine by ADAR enzymes, is treated in the review as part of the same post-transcriptional regulatory landscape. Each modification type can affect different RNA classes, from messenger RNAs and microRNAs to long non-coding RNAs, transfer RNAs and ribosomal RNAs, giving cancer cells an enormous combinatorial toolkit.

The mechanistic heart of the review concerns how these marks enable metastasis. Metastasis is not a single event but a sequence of transitions: tumor cells must detach from the primary mass, invade surrounding tissue, enter the circulation, survive immune attack and shear stress, exit at a distant site, and finally adapt to an alien microenvironment. A recurring theme is that RNA modifications regulate phenotypic plasticity, the capacity of tumor cells to switch between epithelial and mesenchymal states. The epithelial-mesenchymal transition, or EMT, is a prime example. The authors describe how m6A machinery components, particularly METTL3 and the demethylases FTO and ALKBH5, modulate the stability and translation of key EMT transcription factors and signaling mediators, tipping cells toward a motile, invasive, stem-like state or back again. Because these modifications are reversible and rapidly responsive to environmental cues, they provide cancer cells with a fast-acting adaptation mechanism that genetic mutations alone cannot match.

The review also emphasizes that RNA modifications act far beyond the tumor cell itself, remodeling the tumor microenvironment. Cancer-associated fibroblasts, endothelial cells, and infiltrating immune cells all carry their own epitranscriptomic programs that tumors can exploit. In the immune compartment, the authors highlight evidence that m6A modification of transcripts in myeloid-derived suppressor cells and other immune populations shapes the immunosuppressive milieu that shields metastasizing cells from immune destruction. Exosomes and other non-coding RNA species exported from tumor cells carry their modification patterns with them, potentially pre-metastatic niches for incoming tumor cells. This systems-level view reframes metastasis as a conversation between tumor and host that is conducted partly in the language of RNA chemistry, and it suggests that targeting modification enzymes in stromal or immune cells could complement direct attacks on the tumor.

Therapy resistance emerges in the review as the second major arena in which RNA modifications exert decisive influence. The authors detail how modification enzymes regulate the classical determinants of drug response, including the ATP-binding cassette transporter family such as ABCB1 and MDR1, which pump chemotherapeutics out of cells, and the DNA damage response pathways that repair the lesions chemotherapy and radiotherapy inflict. They also describe the connection to cancer stem cells, the slow-dividing, self-renewing subpopulations that survive treatment and seed relapse. RNA modification writers and readers help maintain the stem-like state and the drug-tolerant persister phenotypes that characterize minimal residual disease. In targeted therapy contexts, the review notes involvement of pathways such as Bruton’s tyrosine kinase signaling, illustrating that epitranscriptomic dysregulation is not confined to cytotoxic chemotherapy but extends across the modern therapeutic arsenal.

A particularly compelling section of the review traces how the same modification enzymes can produce opposite effects in different cancer types, a phenomenon the authors use to underscore context dependence. METTL3, for instance, has been reported to act as an oncogenic driver in some tumors by stabilizing pro-metastatic transcripts, while in other settings its depletion promotes tumor progression, reflecting differences in the transcriptome it methylates and the readers available to interpret those marks. This duality has direct clinical consequences: any therapeutic strategy aimed at inhibiting or activating a modification enzyme must account for tumor-type-specific substrate repertoires. The review systematically maps these functional landscapes across diverse cancers, providing what the authors describe as a theoretical foundation for identifying which patients might benefit from which epitranscriptomic intervention.

Translational implications form the forward-looking core of the paper. The authors argue that modification enzymes and their marks hold promise as biomarkers at multiple levels. Aberrant expression of writers such as METTL3, NAT10 or NSUN family members can be measured in tumor biopsies and may correlate with metastatic risk, stage, or predicted drug response. Modification patterns themselves, detectable by emerging high-throughput sequencing methods that map m6A, m5C and other marks transcriptome-wide, could serve as a post-transcriptional analog of the mutational profiling that already guides precision oncology. Circulating tumor RNA carrying characteristic modification signatures might eventually support non-invasive monitoring. The review frames these possibilities as grounded in the demonstrated mechanistic links between specific enzymes and specific metastatic or resistance phenotypes, rather than as speculation.

Therapeutically, the review surveys early efforts to drug the epitranscriptome. Small-molecule inhibitors of FTO have entered preclinical and early clinical evaluation, and compounds targeting METTL3 and NAT10 are under active development. The authors stress that the reversibility of RNA modifications makes them pharmacologically attractive: unlike mutated oncogenes, an enzyme’s activity can be tuned up or down, and because normal tissues also rely on these enzymes, selectivity and therapeutic window will be critical challenges. Combination strategies, pairing epitranscriptomic drugs with immunotherapy, chemotherapy or targeted agents, emerge as a rational approach, particularly given the documented roles of modification enzymes in shaping immune evasion and DNA damage repair. The review also flags technical hurdles, including the need for more precise and affordable mapping technologies and better models of metastatic progression in which to test candidate inhibitors.

What distinguishes this synthesis is its insistence that metastasis and resistance be understood as dynamically plastic processes governed by post-transcriptional regulatory networks rather than as fixed genetic outcomes. By cataloguing the writers, erasers and readers of more than a dozen modification types, connecting them to core signaling pathways and downstream effectors, and tracing their consequences across cancer types, Liu and colleagues provide a reference framework for a field that has grown faster than its unifying concepts. The work was supported by the National Natural Science Foundation of China and Chongqing regional science funds, and the authors acknowledge the use of an AI-assisted language tool for polishing while taking full responsibility for the scientific content. As sequencing technologies mature and first-generation epitranscriptomic drugs advance through trials, the picture that emerges is of cancer’s deadliest behaviors being orchestrated, in significant part, by chemistry that most textbooks treated as trivia barely two decades ago. The review suggests that learning to read, and eventually to rewrite, that chemistry may become a central task of precision oncology.

Subject of Research: The role of RNA modifications in tumor metastasis and therapy resistance

Article Title: Exploring the role of RNA modifications in tumor metastasis and therapy resistance: molecular mechanisms and clinical implications

Article References: Exploring the role of RNA modifications in tumor metastasis and therapy resistance: molecular mechanisms and clinical implications. (n.d.). https://doi.org/10.1186/s12943-026-02788-2

Image Credits: AI Generated

DOI: 10.1186/s12943-026-02788-2

Keywords: RNA modifications, m6A, epitranscriptomics, tumor metastasis, therapy resistance, METTL3, FTO, cancer stem cells, tumor microenvironment, EMT, biomarkers, precision oncology