Evolution of CRISPR Genome Editing and Next-Generation Delivery Technologies to Overcome Refractoriness in Prostate Cancer Treatment
Background
Prostate cancer, a leading cause of cancer-related death in men, is a difficult-to-treat intractable disease due to high molecular heterogeneity within tumor tissues. Current clinical practice primarily relies on Androgen Deprivation Therapy (ADT) and targeted anticancer drugs. While most patients respond to initial treatment, they eventually develop drug resistance, progressing to Castration-Resistant Prostate Cancer (CRPC).
There is an urgent need for personalized therapeutic strategies that can accurately identify and reverse the molecular mechanisms of tumor resistance to treatment. Existing approaches based on gene knockdown or small molecule compounds have faced limitations, such as frequent off-target effects and the inability to fundamentally correct genomic structures. The emergence of molecular tools capable of precisely correcting complex genetic mutations and epigenetic abnormalities has become a top priority in prostate cancer research.
Key Findings
In the field of prostate cancer, genome editing technology is evolving beyond simple cleavage enzymes into precision correction tools. Following the advent of third-generation gene scissors, such as CRISPR-Cas9 nucleases, there is a growing trend to actively incorporate Base Editing, which substitutes single bases without inducing DNA double-strand breaks, and Prime Editing, which induces insertions and deletions by combining reverse transcriptase, into research models. CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) systems, which finely regulate gene expression, are also widely used to identify prostate cancer gene functions.
Researchers identify Androgen Receptor (AR) signaling and DNA Damage Repair (DDR) systems as key molecular pathways driving prostate cancer progression. In particular, loss of the tumor suppressor gene PTEN and the TMPRSS2-ERG fusion gene, a prostate cancer-specific genetic mutation, are decisive factors in disease progression and treatment response. Functional Genomic Screening techniques have achieved success in large-scale identification of synthetic lethality targets that induce selective death only in cancer cells possessing these genetic deficiencies.
Multifaceted therapeutic strategies to overcome drug resistance have also been reported. These include methods such as targeting mutation sites in the AR signaling pathway to neutralize resistance to next-generation androgen receptor inhibitors, or correcting DDR gene mutations to restore sensitivity to radiation and chemotherapy. Epigenome editing technology, which reprograms epigenetic marks, and cell therapy engineering technology, which enhances tumor-killing capabilities by manipulating patient immune cells, are also considered new alternatives.
Research on delivery vehicles to implement therapeutic efficacy in vivo is also advancing rapidly. In addition to viral vectors such as Adeno-Associated Virus (AAV), lipid nanoparticles (LNP) that minimize in vivo immune responses, biodegradable polymer carriers, and extracellular vesicles (EV) are being evaluated as delivery vehicles specific to prostate tumors.
Significance and Outlook
The advancement of CRISPR genome editing tools has provided a turning point, shifting the paradigm of prostate cancer treatment from symptom relief to the correction of causative genes. This is made possible by the implementation of precision oncology, which designs synthetic lethal drug combinations and preemptively blocks resistance mechanisms based on patient genomic information.
However, barriers to overcome still exist. It is pointed out that challenges to be addressed include the risk of genomic toxicity due to in vivo off-target effects, immunogenic reactions that may occur upon repeated administration, and the issue of delivery efficiency in achieving uniform penetration of the correction agent into deep tumor regions. The development of next-generation targeting technologies to overcome the fibrotic microenvironment and high cellular heterogeneity unique to prostate cancer tissue is expected to be the deciding factor for commercialization.
Prostate cancer is one of the leading causes of cancer-related morbidity and mortality among men worldwide and is characterized by substantial molecular heterogeneity and the development of therapeutic resistance. Recent advances in genome-editing technologies, particularly CRISPR-Cas systems, have expanded opportunities for precise investigation and modification of genetic and epigenetic determinants involved in prostate cancer progression. This review comprehensively describes the evolution of CRISPR-based genome-editing tools, including Cas9 nucleases, base editing, prime editing, and CRISPR interference/activation systems, and their applications in prostate cancer models. Particular emphasis is placed on androgen receptor (AR) signaling and DNA damage repair (DDR) pathways, as well as genomic alterations such as PTEN loss and TMPRSS2-ERG fusion, which represent important molecular determinants and therapeutic targets in prostate cancer. The review further examines the application of CRISPR in functional genomic screening, disease modeling, and the identification of synthetic lethal interactions that may reveal novel therapeutic vulnerabilities. Emerging therapeutic strategies, including gene correction, targeting mechanisms underlying resistance to androgen deprivation and AR-directed therapies, sensitization to chemotherapy and radiotherapy, epigenome editing, and immunotherapy engineering, are critically discussed. Advances in CRISPR delivery modalities, including viral vectors, lipid-based nanoparticles, polymeric systems, and extracellular vesicles, are also evaluated with emphasis on tumor targeting, delivery efficiency, safety, and translational challenges. Overall, CRISPR-based technologies show considerable potential to support precision oncology in prostate cancer by enabling molecularly informed therapeutic strategies and addressing treatment resistance, although challenges related to delivery, off-target effects, tumor heterogeneity, immunogenicity, a
This research provides a specific preclinical development roadmap for solving the recurring problem of drug refractoriness in patients with castration-resistant prostate cancer. Pharmaceutical and biotech companies can rapidly design new small molecule compounds or antibody-drug conjugates (ADCs) based on synthetic lethality candidates discovered through large-scale CRISPR screening.
In the clinical stage, promising commercialization scenarios include the direct administration of LNP-based CRISPR therapeutics tailored to genetic mutations in patient biopsy tissues, or the generation of allogeneic CAR-T cells with knocked-out immune checkpoint receptors as part of a combination therapy strategy designed to penetrate the solid tumor microenvironment.