Scholarlink

<p>Therapeutic resistance remains a major obstacle to durable cancer treatment. Tumor cells can survive chemotherapy, targeted therapy, and immunotherapy by activating DNA repair, metabolic adaptation, cancer stemness, epithelial–mesenchymal transition, cell-death escape, and immune evasion. N6-methyladenosine (m6A), the most abundant internal RNA modification in eukaryotic mRNA, has emerged as an important post-transcriptional mechanism that helps coordinate these adaptive programs. METTL3, the catalytic core of the m6A methyltransferase complex, regulates the stability and translation of many resistance-associated transcripts and thereby links RNA modification to cancer therapy response. Increasing evidence shows that METTL3-mediated m6A modification contributes to resistance against platinum agents, taxanes, anthracyclines, antimetabolites, targeted therapies, and immune checkpoint blockade. Pharmacological inhibition of METTL3, especially with the selective inhibitor STM2457, has shown promising activity in preclinical models by reducing m6A-dependent oncogenic programs, restoring drug sensitivity, promoting cell death, and improving anti-tumor immune responses. However, METTL3-targeted therapy also faces important challenges, including context-dependent functions, tumor heterogeneity, possible toxicity in normal tissues, compensatory RNA modification pathways, and the lack of reliable biomarkers for patient selection. In this review, we summarize how METTL3-mediated m6A regulation contributes to cancer therapy resistance and discuss the therapeutic potential and limitations of STM2457 and related METTL3-targeted strategies. We also highlight future directions, including rational combination therapy, transcript-specific biomarkers, and clinical translation of m6A-targeted epitranscriptomic therapy.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

METTL3-dependent m6A modification in cancer treatment resistance and its therapeutic implications

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月5日

查看全文
  • Chuan Jiang,
  • Shuqiang Yang,
  • Jiawei He,
  • Meijia Zhao,
  • Luqian Zhao,
  • Jingjing Wang,
  • Xiaowen Chen,
  • Xin Xu,
  • Hongran Qin

摘要

Therapeutic resistance remains a major obstacle to durable cancer treatment. Tumor cells can survive chemotherapy, targeted therapy, and immunotherapy by activating DNA repair, metabolic adaptation, cancer stemness, epithelial–mesenchymal transition, cell-death escape, and immune evasion. N6-methyladenosine (m6A), the most abundant internal RNA modification in eukaryotic mRNA, has emerged as an important post-transcriptional mechanism that helps coordinate these adaptive programs. METTL3, the catalytic core of the m6A methyltransferase complex, regulates the stability and translation of many resistance-associated transcripts and thereby links RNA modification to cancer therapy response. Increasing evidence shows that METTL3-mediated m6A modification contributes to resistance against platinum agents, taxanes, anthracyclines, antimetabolites, targeted therapies, and immune checkpoint blockade. Pharmacological inhibition of METTL3, especially with the selective inhibitor STM2457, has shown promising activity in preclinical models by reducing m6A-dependent oncogenic programs, restoring drug sensitivity, promoting cell death, and improving anti-tumor immune responses. However, METTL3-targeted therapy also faces important challenges, including context-dependent functions, tumor heterogeneity, possible toxicity in normal tissues, compensatory RNA modification pathways, and the lack of reliable biomarkers for patient selection. In this review, we summarize how METTL3-mediated m6A regulation contributes to cancer therapy resistance and discuss the therapeutic potential and limitations of STM2457 and related METTL3-targeted strategies. We also highlight future directions, including rational combination therapy, transcript-specific biomarkers, and clinical translation of m6A-targeted epitranscriptomic therapy.