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Bibi et al. J Transl Genet Genom 2024;8:119-161 https://dx.doi.org/10.20517/jtgg.2023.50 Page 143

different benefits and drawbacks. For instance, adenoviruses have the ability to transfer large genes and
infect both dividing and non-dividing cells. However, they can cause powerful immune reactions and
temporary expression. Conversely, retroviruses carry the risk of oncogenesis and insertional mutagenesis
even though they can integrate into the host genome and produce stable, long-term expression. To
guarantee the safety and effectiveness of each gene therapy strategy, it is essential to select the best viral
[294]
vector . The creation and design of the viral vectors, guide RNAs, or gene carriers determines the
specificity and delivery of the therapeutic genes. The objective is to precisely and specifically alter or express
a gene in tumor cells while preventing side effects or harm to healthy cells. By modifying their DNA-
binding domains or guide RNAs, clustered regularly interspaced short palindromic repeats (CRISPR)/
CRISPR-associated protein 9 (Cas9), zinc finger nucleases (ZFNs), and transcription activator-like effector
nucleases (TALENs), for instance, can be made to target any desired DNA sequence [269,294] . They must,
however, also be thoroughly examined for specificity and precision because they might result in off-target
breaks or mutations that compromise the integrity or functionality of the genome. Similar modifications or
optimizations are required for viral vectors or gene carriers in order to increase their particularity and
efficacy of delivery to tumor location and to get past some of the obstacles present in the tumor
microenvironment (such as extracellular-matrix, interstitial pressure, and blood flow) . Interplay between
[295]
the host immune system and the viral vectors or therapeutic genes determines the immunological response
and resistance of tumor cells. Certain gene therapy techniques, such as CAR T cell (chimeric antigen
receptor T cell) treatment and cytokine gene therapy, seek to activate the immune system to identify and
combat tumor cells. These methods can exert strong antitumor effects, but they must also avoid triggering
excessive autoimmune reactions or inflammation that could harm healthy tissues . However, alternative
[288]
gene therapy strategies - such as tumor suppressor or suicide gene therapy - strike against the immune
system in an effort to prevent the viral vectors or therapeutic genes from being cleared out or rejected. High
transfection efficiency and robust therapeutic gene expression can be attained with these methods, but
immunosuppression or tolerance that could impair antitumor immunity must be avoided. Furthermore,
tumor cells may acquire resistance mechanisms, such as mutation, epigenetic change, signaling crosstalk, or
microenvironmental adaptability, to evade immune attack or gene therapy-induced cell death. The
molecular and genetic features of each patient's tumor, in addition to their clinical stage and condition,
determine the suitable candidates for each treatment type and the optimal approach to combining them.
Because prostate cancer is a diverse illness with several subtypes and clones with unique genetic and
molecular characteristics, gene therapy response and resistance can vary. Thus, biomarker-based
customized medicine is required to determine which individuals are most suited for each kind of gene
therapy strategy. Patients with DNA repair abnormalities may benefit from CRISPR/Cas9 gene therapy;
those with high levels of HER2 expression may benefit from trastuzumab gene therapy; and those with high
PD-L1 show benefit from CAR T cell therapy [293,296] . The effectiveness of gene therapy must also be enhanced
to overcome resistance, which calls for combination therapy based on synergistic effects. For instance, gene
therapy in combination with immunotherapy, chemotherapy, radiation therapy, or hormone therapy may
produce superior results compared to gene therapy used alone [295,297] .

POTENTIAL VIRAL AND NONVIRAL GENE THERAPIES IN PROSTATE CANCER
The type of genetic material supplied, the amount of genetic material administered, and the administration
method all influence the choice of vector for gene transport. Viruses as carriers offer effective transfection,
long-lasting gene expression, and protection against gene deterioration; however, they can also be highly
poisonous, immunogenic, have poor targeting capacity, and are very expensive. Nonviral vectors,
conversely, do not elicit unfavorable immune responses and are comparatively less toxic, easy to
manufacture, and capable of transmitting huge amounts of genetic material. Nonetheless, they come with
their own set of limitations, such as high susceptibility to intracellular and extracellular barriers, reduced