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

Xian Zhong1,2, Jianmei Mao3,4,5, Jiawei Zhang6

  • 1Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. zhongxian@zju.edu.cn.

Cell Death Discovery
|May 12, 2026
PubMed

Insights

Two key RNA modifications, 5-methylcytidine (m⁵C) and N⁴-acetylcytidine (ac⁴C), regulate tumor biology and immune evasion. Inhibiting their enzymes reverses cancer traits and improves therapy sensitivity.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • Cytidine RNA modifications are crucial in tumor biology, influencing gene expression, metabolism, and immune responses.
  • 5-methylcytidine (m⁵C) and N⁴-acetylcytidine (ac⁴C) are dynamic epitranscriptomic marks with distinct roles in cancer progression.

Purpose of the Study:

  • To investigate the complementary roles of m⁵C and ac⁴C in shaping the tumor microenvironment.
  • To explore the therapeutic potential of targeting m⁵C- and ac⁴C-modifying enzymes in cancer.

Main Methods:

  • Analysis of m⁵C and ac⁴C modifications and their associated enzymes (NSUNs and NAT10).
  • Assessment of the impact of these modifications on gene expression, protein synthesis, and immune cell function.
  • Pharmacologic and genetic inhibition studies to evaluate therapeutic efficacy.

Main Results:

  • m⁵C stabilizes pro-tumorigenic transcripts, promotes glycolysis, and suppresses antitumor immunity.
  • ac⁴C regulates translational efficiency and proteostasis, aiding tumor adaptation to stress.
  • Together, m⁵C and ac⁴C create an immunosuppressive tumor microenvironment by affecting macrophages and T cells.
  • Inhibition of m⁵C and ac⁴C pathways reversed malignant phenotypes and restored sensitivity to therapies.

Conclusions:

  • Cytidine RNA modifications (m⁵C and ac⁴C) establish a two-layer epitranscriptomic architecture that drives tumor plasticity and immunosuppression.
  • Targeting these RNA modification pathways offers a promising strategy for precision RNA-targeted oncology.

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