• CRISPR-Based Activation of Tumor Suppressor Genes: A Novel Strategy in Precision Cancer Therapy
  • Neda Zahmatkesh,1,*
    1. Msc of Molecular Genetic Department of Genetics, Zanjan Branch, Islamic Azad University, Zanjan, Iran.


  • Introduction: Cancer is fundamentally a genetic disorder, arising from the activation of oncogenes and the inactivation or silencing of tumor suppressor genes (TSGs). While much of the research has focused on inhibiting oncogenes, restoring the activity of TSGs presents an equally valuable and complementary therapeutic strategy to hinder cancer progression. In recent years, gene activation technologies—particularly CRISPR-based systems like CRISPRa (CRISPR activation)—have gained attention for their ability to upregulate endogenous genes without altering DNA sequences. This review highlights recent advancements in CRISPRa-mediated activation of tumor suppressor genes and discusses its potential as a novel therapeutic approach for various cancer types.
  • Methods: This narrative review was conducted through targeted keyword searches in databases such as PubMed, Scopus, and Google Scholar. Keywords included: “CRISPRa,” “tumor suppressor gene activation,” “cancer gene therapy,” “dCas9-VP64,” and “CRISPR-based epigenome editing.” The focus was on publications from 2018 to 2025. Studies were selected based on scientific quality, relevance to the topic, and inclusion of either experimental data or clinical insight. Of 63 initially identified articles, 34 were selected for in-depth analysis, comprising original research papers, high-impact reviews, and select clinical studies.
  • Results: CRISPRa systems use deactivated Cas9 (dCas9) fused to transcriptional activators (e.g., VP64, VPR, p300) to induce transcription of endogenous genes without DNA cleavage. Studies show that targeting TSGs such as PTEN, TP53, CDKN1A (p21), and BRCA1 using CRISPRa in breast, lung, and colorectal cancer models led to reduced proliferation, induced apoptosis, and inhibited metastasis. For instance, a 2022 study by Wang et al. demonstrated that CRISPRa-mediated activation of PTEN in glioblastoma cells significantly reduced tumor growth both in vitro and in vivo. Another recent approach involves epigenetic remodeling, where CRISPRa-p300 was used to reverse histone deacetylation and activate TSGs previously silenced by methylation. Despite promising preclinical data, delivery methods remain a challenge, with lipid nanoparticles and adeno-associated virus (AAV) vectors being explored for efficient CRISPRa delivery. Additionally, combinatorial strategies (e.g., CRISPRa + immunotherapy or chemotherapy) show synergistic effects in cancer suppression.
  • Conclusion: CRISPRa offers a promising and innovative approach to cancer therapy by reactivating the body's natural tumor-fighting genes. Unlike conventional gene editing, it doesn't rely on cutting DNA, reducing the risk of unintended mutations. Although the technology is still at an early stage in clinical development, rapid progress is being made in optimizing delivery methods, minimizing off-target effects, and ensuring long-term safety. Looking ahead, large-scale in vivo studies, thorough safety evaluations, and the integration of CRISPRa with personalized or combination therapies will be essential. With continued advancement, CRISPRa-based activation of tumor suppressor genes could become a key pillar in the future of precision oncology.
  • Keywords: CRISPRa, Tumor Suppressor Genes, Gene Activation, Cancer Therapy