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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 133

cancer immunotherapy comes with certain limitations. Depending on the situation and the signaling
pathway involved, EpCAM can exhibit both tumor-promoting and tumor-suppressive functions. For
example, it can act as a tyrosine kinase, promoting tumor growth through the activation of AKT, or as a
[217]
pseudokinase, inhibiting AKT activation via ligand stimulation . Therefore, when developing EpCAM-
targeted medicines, it is crucial to carefully balance these opposing mechanisms. Furthermore, the
variability in EpCAM expression and activity across different prostate cancer subtypes poses another
challenge. EpCAM expression levels can vary from high to low, or even be missing in different prostate
[218]
cancer cells, and its function can change from proangiogenic to antiangiogenic with tumor progression .
Therefore, the ideal timing and dosage of EpCAM-targeted therapy should be carefully evaluated based on
the specific characteristics of each individual case.

Receptor-interacting protein kinase 2
Receptor-interacting protein kinase 2 (RIPK2) is a protein crucial for innate immunity and inflammation.
Additionally, it plays a role in the advancement and metastasis of prostate cancer by maintaining c-Myc, a
protein that promotes tumor development and invasiveness. Therefore, interventions targeting RIPK2 to
degrade c-Myc, such as medicines or gene editing techniques, may hold promise in preventing prostate
cancer [220,221] . Some research suggests that RIPK2 inhibitors have shown beneficial effects in both preclinical
and clinical trials. For instance, the small molecule inhibitor ALW-II-41-27 binds to the ATP-binding site of
RIPK2, impeding its kinase activity. Studies conducted in vitro and in vivo have demonstrated its efficacy in
[220]
inhibiting the proliferation and invasion of prostate cancer cells . Another approach involves KB004, a
humanized monoclonal antibody that induces internalization and degradation of RIPK2 by recognizing an
epitope on its extracellular domain. In mouse models with prostate cancer xenografts, the presence of this
antibody has been demonstrated to slow down tumor development and angiogenesis.

However, there are certain difficulties and restrictions when using RIPK2 as a target for prostate cancer
immunotherapy. Depending on the context and the signaling pathway involved, RIPK2 can serve both
oncogenic and tumor-suppressive purposes. It can either activate AKT as a tyrosine kinase or inhibit its
activation by ligand stimulation as a pseudokinase [221,222] . Therefore, when developing RIPK2-targeted
therapeutics, the balance between these two mechanisms of action should be carefully considered.

Another obstacle is the variability in RIPK2 expression and function across various subtypes and stages of
prostate cancer. In various prostate cancer cells, RIPK2 expression levels can range from high to low, or
even absent, and its function can change from proangiogenic to antiangiogenic as tumors progress . As a
[220]
result, RIPK2-targeted medicines should be carefully tailored in terms of timing and dosage to
accommodate the unique characteristics of each patient.

MAGE
Melanoma antigen gene protein-A11 (MAGE-11), a member of the MAGE family of cancer germ-line
antigens, interacts with the AR NH(2)-terminal FXXLF motif, thereby promoting androgen receptor (AR)
[223]
transcriptional activity . In addition to activating genes necessary for male sex differentiation, high-
affinity androgen binding to the androgen receptor (AR) accelerates the onset and progression of prostate
[224]
cancer . Interactions between human AR transcriptional activity and coregulatory proteins involve the
coactivator melanoma antigen-A11 (MAGE-A11), which is primate-specific and promotes AR
transcriptional activity, thereby contributing to the progression of prostate cancer to castration-resistant/
recurrent prostate cancer (CRPC) . Notably, MAGE-A11's involvement in modulating hormonal signals
[225]
in prostate cancer sets it apart from other type I MAGEs. The binding of MAGE-A11 to the N-terminal
FXXLF motif of the androgen receptor (AR) facilitates SRC/p160 coactivator binding . The
[226]