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Self-sufficient killing of malignant tumors by an engineered cancer-selective gene circuit

Qi Liu1, Qiqi Xiong2, Guanglei Xie3

  • 1Department of Pharmacy, Center for Regenerative and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Zhejiang-Denmark Joint Laboratory of Regeneration and Aging Medicine, Yiwu 322000, China.

Cell Reports. Medicine
|July 23, 2026
PubMed

Insights

Researchers developed a novel cancer-selective gene circuit that targets tumors with specific genetic mutations. This engineered promoter (PETS∗) activates only in cancer cells, enabling precise tumor elimination and improving survival rates in mice with metastatic lung cancer.

Area of Science:

  • Oncology
  • Synthetic Biology
  • Gene Therapy

Background:

  • Achieving cancer-specific gene therapy is challenging due to difficulties in precise tumor cell identification.
  • Existing therapies often lack specificity, leading to off-target effects and limited efficacy.
  • Oncogenic aberrations in E26 transformation-specific (ETS) transcription factors are key drivers in various cancers.

Purpose of the Study:

  • To engineer a therapeutic gene circuit for selective elimination of tumor cells harboring ETS transcription factor aberrations.
  • To develop a cancer-selective promoter that distinguishes tumor cells from healthy tissues.
  • To evaluate the efficacy of the engineered gene circuit in preclinical cancer models.

Main Methods:

  • Utilized a machine learning-guided random forest framework to develop the PETS∗ promoter.
  • Designed the PETS∗ promoter to activate specifically upon ETS overexpression or gene fusion events.
  • Employed adenoviral vectors for in vivo delivery of the PETS∗-driven gene circuit.
  • Assessed tumor-restricted viral replication, tumor suppression, and survival in mouse models.

Main Results:

  • The PETS∗ promoter demonstrated high cancer specificity, activating only during ETS aberrations and remaining inactive in healthy tissues.
  • Adenoviral delivery of the PETS∗-driven gene circuit resulted in tumor-restricted viral replication in vivo.
  • Sustained tumor suppression and complete survival were observed in mice treated with the engineered gene therapy.
  • Intratracheal delivery achieved long-lasting control of metastatic lung tumors for over 140 days.

Conclusions:

  • The engineered PETS∗ promoter represents a significant advancement in achieving cancer specificity for gene therapies.
  • This synthetic biology approach overcomes key limitations in oncolytic virotherapy.
  • The developed gene circuit holds promise for future cancer treatment strategies, particularly for ETS-driven malignancies.
Keywords:
ETS transcription factorsadenovirus deliverycancer selective oncolytic virotherapycancer-specific promotersynthetic gene circuit

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