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Page 262 Thomas et al. J Transl Genet Genom 2024;8:249-77 https://dx.doi.org/10.20517/jtgg.2024.15

mechanistic underpinnings that resulted in the limited efficacy of DC vaccine for clinical management of
prostate cancer are described further in this review. However, several vaccine targets are currently under
evaluation against prostate cancer, including oncofetal antigen-5T4, carcinoembryonic antigen (CEA), PSA,
prostate-specific membrane antigen (PSMA), survivin, tumor-associated antigens (TAA), and personalized
neoantigens. These selected proteins serve as targets due to their high expression levels in cancer cells
compared to their normal counterparts .
[228]

Other prominent strategies in prostate cancer immunotherapy involve the use of immune modulators to
disrupt immune checkpoints, such as PD-1/PD-L1 and CTLA-4, exploited by cancer cells to evade immune
[196]
detection and responses, often leading to T-cell exhaustion . In addition to these well-established targets,
ongoing clinical investigations in other urological cancer types, such as bladder cancer, explore immune
modulators targeting the immunosuppressive activity of CD73, indoleamine 2,3-dioxygenase (IDO), and
lymphocyte activation gene 3 (LAG3) [229-232] (Clinical Trial Registration Numbers NCT03454451,
NCT05843448, NCT04586244). Immunomodulation treatments also include the activation of co-
stimulatory pathways to promote or enhance T-cell functions by downregulating immunosuppressive
components like Tregs in the TME. Key targets in this category include inducible co-stimulator (ICOS),
OX40, Toll-like receptors (TLRs), CD137, and IL-2/IL-2R [233-236] .

Adoptive or cell-based immunotherapy represents another autologous approach, where the patient’s
immune cells, such as T cells, are isolated, expanded in vitro, and modified with chimeric antigen receptors
(CARs) that can specifically target antigens expressed by tumor cells, thereby eliminating them. Adoptive
immunotherapy targets currently under evaluation for prostate cancer include prostate stem cell antigen
[237]
(PSCA) and PSMA . Beyond T cells, both NK and tumor-infiltrating lymphocytes (TILs) can also be
enhanced and reintroduced into patients [238,239] . Monoclonal antibodies constitute another class of treatments
developed to block specific cell membrane receptors from binding to its target ligand, thereby impeding its
functional impact on cancer growth and proliferation. Commonly targeted membrane receptors in prostate
cancer include delta-like proteins (DLL), Notch, human epidermal growth factor receptor 2 (HER2), and
tumor-associated calcium signal transducer 2 (TROP2) [240-242] . Antibodies can also be modified to carry
[243]
cytotoxic payloads, specifically chemotherapeutics, for their active delivery to tumors . Bi-specific T-cell-
[244]
engaging antibodies or BiTEs bind to cancer cells and T cells, activating the latter . Oncolytic viral therapy
involves the use of different DNA (Adenovirus and Herpes simplex virus) and RNA (Reovirus) viruses,
often modified to infect tumor cells and induce cell death. This approach can elicit an immune response
that further aids in the elimination of both localized and metastatic tumors .
[245]
While appealing, the immunosuppressive and "cold" TME in prostate cancer poses a significant challenge
for the immunotherapy strategies described. Therefore, emerging therapeutic approaches aim to target both
cancer cells and the TME. One strategy involves directly targeting stromal markers upregulated in the TME,
such as FAP, which is associated with poor prognosis in various solid tumors. Targeting FAP-expressing
CAFs using CAR-T therapy shows promise in improving tumor-targeted cytotoxicity of CAR-T cells
targeting solid tumors. In summary, therapies targeting both cancer cells and the TME hold the potential
for effectively treating prostate cancer and improving patient outcomes. Table 1 provides a summary of
various immunotherapies currently under evaluation in clinical trials, while Table 2 outlines potential
therapies for targeting tumor stroma [20,245,263] .

MACROPHAGE THERAPY FOR METASTATIC CASTRATION RESISTANCE PROSTATE
CANCER
Immunotherapy exhibits limited efficacy in advanced prostate cancer patients with mCRPC, mainly due to