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  • Precision Genome Editing in Oncology through Base and Prime Editing: Molecular Foundations, Genomic Fidelity, and Therapeutic Prospects

  • Alireza Nikkhah,1 Mohammad Hashemabadi,2 Abbas Hajizade,3,*
    1. Biology Research Center, Faculty of Basic Sciences , Imam Hossein University Tehran, Iran
    2. Department of Cellular and Molecular Biology, Faculty of Life science and Biotechnology, Shahid beheshti university, Tehran, Iran
    3. Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran


  • Introduction: CRISPR-Cas9 has revolutionized cancer biology by enabling programmable genome editing for tumor modeling, functional genomics, and therapeutic development. However, conventional Cas9 editing relies on DNA double-strand breaks (DSBs), which are repaired primarily through non-homologous end joining (NHEJ) or homology-directed repair (HDR). DSBs may induce indels, large genomic rearrangements, chromosomal abnormalities, and activation of p53-dependent DNA damage responses, while HDR remains inefficient in many clinically relevant cells. These limitations have driven the development of precision genome-editing technologies, particularly cytosine and adenine base editors (CBEs and ABEs) and prime editors (PEs), which can introduce defined genetic changes without requiring conventional DSBs. This review evaluates their molecular mechanisms, oncological applications, genomic safety, and translational challenges.
  • Methods: A narrative review of recent peer-reviewed literature was conducted focusing on Base Editing and Prime Editing technologies in cancer research and therapeutic applications. Studies addressing the molecular architecture and mechanisms of CBEs, ABEs, and PEs; generation and correction of cancer-associated mutations; CRISPR-mediated gene inactivation; and genomic safety and in vivo delivery were considered. Particular attention was given to studies involving clinically relevant cancer genes, including KRAS, TP53, and PIK3CA, as well as technological developments aimed at improving editing efficiency and reducing unintended outcomes.
  • Results: The reviewed evidence demonstrates that Base Editing and Prime Editing substantially expand the precision and versatility of CRISPR-based genome engineering. CBEs(Cytosine Base Editors) enable targeted C→T substitutions, whereas ABEs(Adenine Base Editors) facilitate A→G conversion through deamination of adenine to inosine. Prime Editing further broadens the editing spectrum by enabling all 12 possible base substitutions as well as short insertions and deletions without donor DNA or conventional DSBs. These technologies have been applied to cancer research for generating premature termination codons, modeling oncogenic mutations, and correcting pathogenic variants. Base editing has been used to engineer cancer-relevant mutations such as PIK3CA H1047R and to investigate correction of KRAS and TP53 mutations. Prime Editing has similarly enabled precise modeling and experimental correction of mutations including KRAS G12D and TP53 variants. However, the reviewed studies also identify important limitations, including bystander editing, DNA- and RNA-level off-target activity, variable editing efficiency, dependence of Prime Editing on cellular mismatch-repair pathways, and difficulties associated with in vivo delivery. Advances such as engineered editors, narrower editing windows, PE3b, PE4/PE5 systems, compact editors, dual-vector approaches, lipid nanoparticles, and RNP delivery are being investigated to address these limitations.
  • Conclusion: Base Editing and Prime Editing represent promising next-generation genome-editing platforms for precision oncology. By reducing reliance on DSBs, they offer important advantages for modeling, interrogating, and potentially correcting cancer-associated genetic alterations. Nevertheless, their clinical translation requires further optimization of editing specificity, bystander and off-target control, genomic safety, editor duration, and tumor-selective delivery. Continued development of compact and high-fidelity editors, improved guide-RNA design, and advanced delivery systems will be essential for translating these technologies from experimental cancer models toward safe and individualized therapeutic applications.
  • Keywords: CRISPR-Cas system- Base Editing- Prime Editing- Precision Oncology- Genome Editing

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