N7-methylguanosine (m 7 G) is distributed across several RNA classes and regulates distinct stages of gene expression. The best-characterized form is the 5′cap of messenger RNA, although m 7 G also occurs in transfer RNA, ribosomal RNA, internal messenger RNA, circular RNA, and transfer RNA-derived small RNAs. Cancer-associated m 7 G dysregulation therefore cannot be ascribed to a single enzyme or molecular outcome. The strongest causal evidence concerns the METTL1-WDR4 complex, which modifies transfer RNA and reshapes codon-biased translation, promoting proliferation, metastasis, metabolic adaptation, stress tolerance, and treatment resistance. Studies of internal messenger RNA m 7 G report reader-dependent effects on stability, decay, translation, and stress-granule partitioning. Cap biochemistry is established, whereas catalytic cancer mechanisms involving ribosomal RNA remain less resolved. In preclinical models, these pathways connect tumor-cell adaptation with stromal communication, immune evasion, and treatment response. The biological effects of m 7 G vary with the modified RNA and the proteins favored by translation; tumor-restrictive activity emerges when altered tRNA modification increases the production of cell-cycle inhibitory proteins. This review organizes established and emerging mechanisms by RNA compartment and examines the substrate-dependent balance between tumor promotion, tumor restriction, and treatment sensitivity. It also evaluates biomarker strategies, emerging pharmacological and RNA-directed interventions, and the methodological standards needed to distinguish direct m 7 G-dependent effects from regulator expression correlations. A site-resolved, substrate-specific understanding of m 7 G may reveal translational dependencies that are actionable without disrupting essential RNA metabolism in normal tissues.
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Tian et al. (2026) studied this question.
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