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<p>Transcription factors (TFs) occupy a central position in cancer biology, functioning as master regulators that translate genetic, epigenetic and environmental cues into cell fate decisions, proliferation, survival, and therapy response. Historically deemed “undruggable” owing to their lack of catalytic sites, conformational flexibility, and engagement in broad protein-DNA and protein-protein interfaces, TFs were long considered beyond the reach of conventional pharmacology. Over the past decades, advances in structural biology, chemical biology, epigenetics, and nucleic acid therapeutics have begun to overcome these challenges, revealing actionable vulnerabilities within TF networks. This review synthesizes current understanding of TF function in tumorigenesis, moving from mechanistic insights at the level of individual TFs to the higher-order organization of transcriptional regulatory networks. It further assesses emerging therapeutic strategies aimed at perturbing aberrant TF activity, encompassing direct inhibition, targeted protein degradation, modulation of TF-cofactor interactions, and nucleic acid-based interventions. We further highlight exemplary TFs and their typical targeting strategies, including Myelocytomatosis oncogene (MYC), Signal transducer and activator of transcription 3 (STAT3), Catenin beta-1 (β-catenin), Yes-associated protein/Transcriptional coactivator with PDZ-binding motif/Transcriptional enhanced associate domain (YAP/TAZ/TEAD), Estrogen receptor/Androgen receptor (ER/AR), and Phosphatase and tensin homolog/Protein kinase B/Forkhead box O (PTEN/AKT/FOXO), which illustrating mechanistic understanding of transcriptional regulation drives therapeutic development and enables genomics-guided precision oncology. By unifying mechanistic insight with pharmacological innovation, we aim to provide a conceptual framework for targeting the transcriptional architecture of cancer and charting paths toward next-generation transcription-directed therapies.</p>

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Transcription factor targeting strategies in cancer: mechanisms, challenges and cutting-edge progress

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月14日

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  • Hui Chen,
  • Rong Fu,
  • Zhao-qiu Wu

摘要

Transcription factors (TFs) occupy a central position in cancer biology, functioning as master regulators that translate genetic, epigenetic and environmental cues into cell fate decisions, proliferation, survival, and therapy response. Historically deemed “undruggable” owing to their lack of catalytic sites, conformational flexibility, and engagement in broad protein-DNA and protein-protein interfaces, TFs were long considered beyond the reach of conventional pharmacology. Over the past decades, advances in structural biology, chemical biology, epigenetics, and nucleic acid therapeutics have begun to overcome these challenges, revealing actionable vulnerabilities within TF networks. This review synthesizes current understanding of TF function in tumorigenesis, moving from mechanistic insights at the level of individual TFs to the higher-order organization of transcriptional regulatory networks. It further assesses emerging therapeutic strategies aimed at perturbing aberrant TF activity, encompassing direct inhibition, targeted protein degradation, modulation of TF-cofactor interactions, and nucleic acid-based interventions. We further highlight exemplary TFs and their typical targeting strategies, including Myelocytomatosis oncogene (MYC), Signal transducer and activator of transcription 3 (STAT3), Catenin beta-1 (β-catenin), Yes-associated protein/Transcriptional coactivator with PDZ-binding motif/Transcriptional enhanced associate domain (YAP/TAZ/TEAD), Estrogen receptor/Androgen receptor (ER/AR), and Phosphatase and tensin homolog/Protein kinase B/Forkhead box O (PTEN/AKT/FOXO), which illustrating mechanistic understanding of transcriptional regulation drives therapeutic development and enables genomics-guided precision oncology. By unifying mechanistic insight with pharmacological innovation, we aim to provide a conceptual framework for targeting the transcriptional architecture of cancer and charting paths toward next-generation transcription-directed therapies.