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<p>Cytidine RNA modifications have emerged as key regulators of tumor cancer biology, linking transcriptional control to metabolic adaptation and immune evasion. Among them, 5-methylcytidine (m⁵C) and N⁴-acetylcytidine (ac⁴C) represent dynamic and functionally complementary epitranscriptomic marks that operate through distinct regulatory layers. m⁵C, catalyzed by the NSUN family methyltransferases, primarily stabilizes pro-tumorigenic transcripts, enhances glycolysis, and suppresses antitumor immunity through modulation of cytokine and checkpoint pathways. In parallel, ac⁴C, mediated by the acetyltransferase NAT10, fine-tunes translational efficiency and proteostasis, enabling tumor cells to adapt to metabolic and therapeutic stress. Together, these modifications cooperatively remodel the tumor immune microenvironment by driving macrophage polarization, T-cell exhaustion, and attenuation of interferon signaling, establishing a durable immunosuppressive niche. Notably, pharmacologic or genetic inhibition of m⁵C- and ac⁴C-modifying enzymes reverses malignant phenotypes and restores sensitivity to immune checkpoint and metabolic therapies. Elucidating this two-layer cytidine epitranscriptomic architecture unveils new epigenetic dimensions of tumor plasticity and offers promising avenues for precision RNA-targeted oncology.</p>

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Epitranscriptomic control of cancer: the emerging roles of m⁵C and ac⁴C RNA modifications

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Xian Zhong,
  • Jianmei Mao,
  • Jiawei Zhang

摘要

Cytidine RNA modifications have emerged as key regulators of tumor cancer biology, linking transcriptional control to metabolic adaptation and immune evasion. Among them, 5-methylcytidine (m⁵C) and N⁴-acetylcytidine (ac⁴C) represent dynamic and functionally complementary epitranscriptomic marks that operate through distinct regulatory layers. m⁵C, catalyzed by the NSUN family methyltransferases, primarily stabilizes pro-tumorigenic transcripts, enhances glycolysis, and suppresses antitumor immunity through modulation of cytokine and checkpoint pathways. In parallel, ac⁴C, mediated by the acetyltransferase NAT10, fine-tunes translational efficiency and proteostasis, enabling tumor cells to adapt to metabolic and therapeutic stress. Together, these modifications cooperatively remodel the tumor immune microenvironment by driving macrophage polarization, T-cell exhaustion, and attenuation of interferon signaling, establishing a durable immunosuppressive niche. Notably, pharmacologic or genetic inhibition of m⁵C- and ac⁴C-modifying enzymes reverses malignant phenotypes and restores sensitivity to immune checkpoint and metabolic therapies. Elucidating this two-layer cytidine epitranscriptomic architecture unveils new epigenetic dimensions of tumor plasticity and offers promising avenues for precision RNA-targeted oncology.