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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 121

anatomical targeting, benefiting both direct cytotoxic and immunotherapy-based gene therapies [22,23] .
Moreover, certain solid tumors, including prostate cancer, exhibit overexpression of the osteocalcin gene,
[24]
making it a significant target for gene therapy interventions .

The way a patient responds to treatment is affected by various factors, including intra-tumor differences
and previous therapies. This highlights the need for personalized and combined treatments, emphasizing
their vital role in future strategies for successful immunotherapy and gene therapy. This overview delves
into current and emerging treatments for prostate cancer, with a focus on immunotherapy and gene
therapy. It addresses challenges posed by the unique immunosuppressive tumor microenvironment,
discussing active and passive immunotherapy, adoptive T-cell treatment, and immune checkpoint
inhibitors. The review explores the roles of immune cells (MDSCs, Tregs, and TAMs) in prostate cancer
progression and treatment resistance and identifies key target proteins and antigens. Additionally, it
provides insights into gene therapy, encompassing gene editing techniques and delivery methods.

CURRENT CHALLENGES IN IMMUNOTHERAPY RESPONSES IN PROSTATE CANCER
Prostate cancer progresses slowly compared to other malignancies, rendering it an optimal target for
immune therapy. However, clinical trials employing various immune therapy methods, such as active
immunotherapy, passive immunotherapy, adoptive T-cell treatment, and the combination of immune
checkpoint inhibitors with chemotherapy, have shown limited effectiveness in metastatic castration-
resistant prostate cancer (mCRPC) . The in-effectiveness of recent immune therapy in metastatic prostate
[25]
[26]
cancer might stem from the compromised immune system in these patients . They often exhibit defective
cellular immunity, reduced natural killer (NK) cell activity, and lower circulating T-cell frequencies . The
[27]
tumor microenvironment in prostate lesions creates an unfavorable niche for immune cells [28-30] , limiting the
efficacy of immunotherapy [31,32] . Studies have indicated reduced infiltration of tumor-infiltrating CD8+ T
cells in patients treated with antiandrogen like abiraterone . Immune checkpoint inhibitors, although they
[33]
block PD-1 and PD-L1 interactions, face challenges due to different kinds of immune-suppressive traits
within the prostate tumor microenvironment, such as higher plasma TTGF-β concentration and increased
suppressive cells like TAM, Tregs, and MDSCs [34-38] . Prostate cancer often exhibits limited infiltration of
efficient immune cells, referred to as a “cold” tumor, due to weakened cellular immunity and a highly
immune-suppressive tumor microenvironment. It is unclear whether the absence of immune infiltration
stems from the failure of effector natural killer cells and T cells to home in on the tumor. Additional
potential resistance pathways have been suggested, including immunological tolerance [39,40] and decreased
[41]
mutational tumor load, indicating resistance to immunotherapy in male subjects with prostate cancer .
Several Phase-III clinical trials and active immunotherapy trials have been conducted for prostate cancer
subjects, although their effectiveness remains limited. Emerging evidence from small-scale clinical trials has
shown promise, and CAR-T therapy breakthroughs have transformed the treatment landscape for
refractory malignancies. Prostate cancer's pleiotropic effects, including leukocyte infiltration, hormonal
escape, angiogenesis, development, and endothelial-mesenchymal transition, are linked to cytokines and
chemokines. Targeting the chemokine system and immune cells is essential to developing effective
immunotherapies for prostate cancer. Despite challenges, there is cautious optimism about the future of
immunotherapy for advanced prostate cancer [42,43] .

IMMUNE EVASION IN PROSTATE CANCER
Tumors have evolved ways to prevent identification by the immune system. Myeloid-derived suppressor
cells (MDSCs), T regulatory cells (Tregs), and tumor-associated macrophages (TAMs), which block effector
T-cell functions, can all be attracted to and grow in the tumor microenvironment [44,45] [Figure 1].