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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 139

5. Due to the low incidence of DNA repair errors, there are not many mutations in prostate cancer that
[233]
could increase its susceptibility to checkpoint inhibitors .
6. The intricate relationship between androgen receptor and prostate cancer hinges on testosterone, which is
crucial for both development and survival. Testosterone can affect the expression and function of immune
cells and molecules. However, despite this understanding, the currently available immunotherapies licensed
for prostate cancer (sipuleucel-T and pembrolizumab) have only demonstrated minor improvements in a
limited subset of patients, underscoring the inadequacy of effective immunotherapies for prostate
cancer [264-266] .

7. Immune checkpoint inhibitors that stop the immune cells with inhibitory receptors, such as PD-1 and
CTLA-4, protect the cancer cells from the attack or inhibitory act of immune cells. Checkpoint blockade has
demonstrated efficacy in treating certain cancers such as lung and melanoma cancer, but its effectiveness in
[267]
prostate cancer has been limited . Additionally, melanoma of unknown primary (MUP) remains
biologically ill-defined, as compared to the classical melanoma of known primary (MKP). Recent research
has revealed that patients with MUP sites seem to present better outcomes compared to those with stage-
matched MKP, probably due to higher immunogenicity as reflected in the immunologically mediated
primary site regression. MUP patients on immunotherapy probably display better outcomes compared to
the MKP subset . Researchers investigated the possible reasons for this resistance and found that it is
[268]
driven by immune cells called macrophages. They showed that macrophages in prostate tumors can
produce a protein called IL-23, which can activate a signaling pathway called STAT3 in tumor cells. STAT3
can then induce the efficacy of genes that increase tumor survival and inhibit checkpoint inhibitors. In
preclinical models of prostate cancer, the researchers also demonstrated that inhibiting IL-23 or STAT3
could improve the effectiveness of checkpoint blockade .
[267]

The influence of co-morbidity on the response of immunotherapy in prostate cancer is one of the causes of
immunotherapy failure. In a study conducted in 2020, researchers found that 11% of the patients included
had a history of diabetes. Further investigations into a national sample revealed that 13% of prostate cancer
patients had this condition. Additionally, hypertension was mentioned by 56% of patients who underwent
radical prostatectomy for prostate cancer. Within this sample, 18 out of 42 patients were diagnosed with
hypertension. Nonetheless, a national sample of prostate cancer patients showed that 30.5% of them had at
least one co-morbidity [268,269] . Contrary to other studies, such as the one by Edwards et al., which predicted
co-morbidity conditions included in the Charlson Co-Morbidity Index, excluding hypertension, our higher
overall rates of co-morbidity may be due to the inclusion of hypertension [270,271] . Considering earlier research
showing that men undergoing radical prostatectomy have a higher chance of biochemical recurrence post-
treatment, the absence of hypertension in studies analyzing the prognosis of prostate cancer may be a
noteworthy oversight [272,273] .

CURRENT STATUS OF GENE THERAPY IN PROSTATE CANCER
After the discovery of the DNA helical structure, there was a global technological explosion, leading to the
development of numerous cutting-edge technologies that are currently being implemented in therapeutic
settings. Several molecular approaches that aid in editing DNA codes and post-transcriptional mRNA
modification have come over the past few decades. Delivering certain genetic material to alter a gene
product's encoding or a tissue's biological characteristics in order to treat a variety of illnesses is known as
gene therapy . The drawbacks of using peptides in recombinant therapeutics, including limited
[274]
bioavailability, instability, extreme toxicity, clearance rates, and expensive production costs, are addressed
via gene therapy . Gene treatments work through a variety of techniques, such as administration of newly
[275]