Precision prime editing of TP53 mutations for functional tumor suppression in colorectal cancer

Colorectal cancer (CRC) is a major global health concern, with high mortality due to genetic heterogeneity and resistance to treatment. Tumor Protein p53 (TP53) mutations are also among the most important molecular changes that can disrupt genomic stability and facilitate tumor progression, so it is a critical target for precision-based interventions.

This review aims to discuss the future potential of prime editing as a new generation of genome engineering to identify precise approaches to correct TP53 mutations in colorectal cancer.

A focused literature review was conducted on PubMed, Scopus, Web of Science, and Google Scholar for articles published between the years of 2010 and 2026. The keywords used in the search were CRC, TP53 mutation, prime editing, Prime Editing Guide RNA (pegRNA), CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9), and precision oncology. Studies were screened for experimental, mechanistic, and translational, and the focus was on mutation-specific editing, delivery platforms, organoid validation, clinically relevant barriers, etc. RESULTS/DISCUSSION: Prime editing is a programmable search-and-replace method that does not involve two single-stranded Deoxyribonucleic Acid (DNA) breaks, resulting in fewer Insertions/deletions (indels) and greater precision compared with traditional CRISPR-Cas9 approaches. Recent systems like Prime Editor Max (PE_max), PE5/PE5_max, engineered pegRNAs, twin prime editors, PrimeDel, and PASTE have enhanced the efficiency, range, and flexibility. Hotspot and organoid studies suggest that variants of TP53, particularly R175H, R248Q/W, R273 H/C, and R282W, can be repaired. But cargo size, delivery specificity, tumor heterogeneity, varying cargo editing efficiency, cargo recognition by the immune system, and off-target risk are all barriers to clinical translation.

Precision oncology with prime editing has the potential to be a useful tool for CRC, though optimized delivery, thorough preclinical testing, and safety monitoring will be required for therapeutic adoption.

This review combines TP53 hotspot biology, recent breakthroughs in prime editing technology, and CRC-specific translational challenges, and provides a step-by-step approach to its clinical application in a unique way.