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Targeted suppression of tumor growth by CREPT promoter-driven diphtheria toxin fragment A

Cancer Gene Therapy volume 33, pages 145–154 (2026)Cite this article

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Abstract

Despite significant advancements in diagnosis and treatment, cancer remains a leading cause of mortality globally. Cancer gene therapy has emerged as a promising strategy, with numerous clinical trials demonstrating its efficacy in targeting tumor cells, vasculature, and immune components. However, precise and selective gene expression regulation remains a challenge. In this study, we demonstrated that the CREPT (cell-cycle related and expression-elevated protein in tumor) promoter holds great potential for targeted cancer gene therapy. CREPT, a tumor-promoting protein as a positive regulator of gene transcription, is highly expressed across various cancer types while exhibiting minimal expression in normal tissues. The CREPT promoter mediated robust and tumor-selective transgene expression in vivo following both local and systemic administration, with only minimal off-target expression detected in blood and none in normal organs. Leveraging this specificity, we engineered an adenovirus encoding diphtheria toxin fragment A under CREPT promoter regulation. This construct was selectively expressed and inhibited protein synthesis, leading cancer cell death in vitro and in vivo. These findings demonstrate that the CREPT promoter may serve as a useful regulatory element for the development of targeted cancer gene therapy.

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Fig. 1: CREPT is upregulated in COAD and BRCA.
Fig. 2: The CREPT promoter is hyperactive in COAD and BRCA cell lines.
Fig. 3: The CREPT-EGFP adenovirus preferentially expressed in tumor tissues in vivo.
Fig. 4: Production of DTA-expressing adenovirus in mutant 293 A cell line.
Fig. 5: The CREPT-DTA adenovirus selectively kills cancer cells in vitro.
Fig. 6: The CREPT-DTA adenovirus significantly impairs the growth of subcutaneous xenograft tumors.

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Data availability

Data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Kuancan Liu from Central Laboratory, Xiang’an Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, China for providing plasmid pBSDT-AII.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82430087 to ZC) and grants from the Science and Technology Bureau of Jiaxing city, Zhejiang, China (2024AZ30004 to SJ).

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Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, School of Basic Medical Sciences, Tsinghua Medicine, Tsinghua University, Beijing, China

    Jingya Li, Mengdi Li, Guancheng Jiang, Yinyin Wang, Zhijie Chang, Jian Sheng & Fangli Ren

  2. School of Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China

    Jingya Li

  3. Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Affiliated to Shandong First Medical University, Jinan, China

    Wenchen Wang

  4. Department of General Surgery, The First Medical Centre of Chinese PLA General Hospital, Beijing, China

    Wenchen Wang

  5. Department of Gastroenterology, The Seventh Medical Center of Chinese PLA General Hospital, Beijing, China

    Jianqiu Sheng

  6. Department of Research and Teaching, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China

    Jian Sheng

  7. Senior Department of Gastroenterology, The First Medical Center of Chinese PLA General Hospital, Beijing, China

    Mingyang Li

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Contributions

JL, LMD, ZC, and FR conceived and designed the project. JL, WW, and GJ designed and performed experiments. JL acquired, analyzed, and visualized data. JL wrote the original draft of the paper. LMD, YW, SJQ, ZC, SJ, LMY and FR revised the manuscript.

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Correspondence to Jian Sheng, Mingyang Li or Fangli Ren.

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The authors declare no competing interests.

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All animal experiments were performed in accordance with relevant guidelines and regulations and were approved by the Institutional Animal Care and Use Committee of Tsinghua University. The animal work was conducted under the protocol 20-CZJ-2. The research involving human participants was approved by the Clinical Ethics Committee of the Chinese PLA General Hospital (Approval Number: S2022-610-01). Informed consent was obtained from all participants.

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Li, J., Li, M., Wang, W. et al. Targeted suppression of tumor growth by CREPT promoter-driven diphtheria toxin fragment A. Cancer Gene Ther 33, 145–154 (2026). https://doi.org/10.1038/s41417-025-00961-1

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