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Page 120 Bibi et al. J Transl Genet Genom 2024;8:119-161 https://dx.doi.org/10.20517/jtgg.2023.50

INTRODUCTION
Prostate cancer ranks as the second most common type of human cancer globally, and in the United States
alone, there were 288,300 new active cases and 34,700 deaths recorded in 2023. Prostate cancer constituted
around 21% of male cancer cases that year . While surgery, chemotherapy, and/or radiotherapy remain
[1]
primary treatments for many solid tumors, combining immunotherapy with other medications is enhancing
patient survival rates. Research advancements in immunotherapy for various solid tumors, including
prostate cancer, show promising results. Prostate cancer studies indicate the significant role of inflammation
[2-5]
in its growth and increment, with molecular heterogeneity defining the disease stages . Capturing and
knowing how immunity reacts to immunomodulatory drugs in prostate cancer can aid in developing
innovative combination therapies. Typically, localized cases are managed with procedures such as radical
prostatectomy or radiotherapy, followed by ongoing monitoring through PSA tests. There is a well-
documented overall survival benefit of adding ADT to radiotherapy in localized prostate cancer. To date,
prospective randomized trials have not investigated the use of ADT alongside stereotactic ablative
radiotherapy (SABR). As such, there is no consensus as to the use and timing of ADT with SABR to treat
hormone-sensitive oligometastatic prostate cancer. There is robust evidence indicating that androgen
receptors activate DNA repair pathways, which provides a rationale behind the use of ADT with SABR for
hormone-sensitive prostate oligo-metastases. Chronic inflammation, often linked to prostatitis-induced
cellular and genetic damage, strongly influences prostate cancer development and progression .
[6,7]

Prostate cancer is often termed a “cold tumor” due to its immunosuppressive surroundings. In this
environment, infiltrating lymphocytes hinder the activeness of T-effector cells, promoting the increment of
prostate cancer. Biopsy samples reveal that these lymphocytes typically exhibit T helper 17 and T regulatory
phenotypes, which impede the patient’s immune response against tumor and the production of autoreactive
[8,9]
T cells . Prostate cancer with weaker T-cell shortlisting and filtration power, a less suppressive tumor
microenvironment (TME), and fewer mutations is less responsive to immunotherapy. Despite these
challenges, a subset of prostate cancer patients display immunogenic traits. Recent examples of positive
responses to immunosuppressive drugs (ISDs) or their combinations include patients with more expression
of PD-L1 tumor, CDK12 mutational changes, significant tumor-mutational burden, high microsatellite
instability (MSI) cancers, mismatch repair-deficient (dMMR) individuals [10,11] . However, unlike head and
neck cancer, non-small-cell lung cancer, melanoma, and renal cell carcinoma, prostate cancer shows limited
[12]
success in immunity responses to treatment due to its immunosuppressive nature . Biallelic inactivation of
CDK12 is associated with a unique genome instability phenotype. The CDK12-specific focal tandem
duplications can lead to the differential expression of oncogenic drivers, such as CCND1 and CDK4 . As
[13]
such, there is a possibility of vulnerability to CDK4/6 inhibitors for CDK12-mutated tumors. Moreover, the
CDK12 aberrations may be used next to mismatch repair deficiency, as a biomarker of treatment
response . This highlights the rationale for the combination therapeutic strategy of immune checkpoint
[14]
blockade and CDK4/6 inhibition in clinical trials [15-17] . Immunotherapy trials aim to target T cell infiltration
and the mutational load of prostate cancer cells, and harness the combined power of treatments to
counteract the inhibitory tumor microenvironment (TME) [10,18] .

Gene therapy involves the use of specialized medications to target specific genes, either by modifying the
genetic code responsible for certain outcomes or by altering tissue characteristics, with the aim of treating
various illnesses. Initially, gene therapy focused on simple genetic disorders such as severe combined
immunodeficiency, aiming to replace defective genes [19,20] . So far, the advent of cancer gene therapy brought
new perspectives and techniques, recognizing cancer as a condition involving both germ cell and somatic
[21]
cell genetic changes . Prostate cancer, particularly early-stage cases detectable through blood tests, can be
targeted effectively using gene therapies, especially via intra-prostatic injections. This method allows precise