Multidimensional explanations and future perspectives on the limited efficacy of immunotherapy in prostate cancer

As immunotherapy continues to push the envelope, it has had transformative success in malignancies such as melanoma and lung cancer. However, in contrast to these cancers, implementing immunotherapy in prostate cancer (PCa) still presents considerable difficulties. PCa itself is not sensitive to immunotherapy. The low response rate of PCa to immunotherapy cannot be attributed to a single mechanism. Instead, it results from the interplay of multiple adverse factors. These include the tumor's inherently low immunogenicity and the highly immunosuppressive properties of its tumor microenvironment. Taken together, these features create a "perfect storm" that severely limits the efficacy of immunotherapy. In this review, we comprehensively assess the latest advances in PCa immunotherapy, encompassing cancer vaccines, immune checkpoint inhibitors (ICIs), chimeric antigen receptor T cell (CAR-T) therapy, and various combination regimens. We also summarize their limited efficacy observed in clinical practice to date. Furthermore, we explore the underlying mechanisms contributing to the limited effectiveness of immunotherapy in PCa, with a focus on intrinsic molecular features, the immunosuppressive microenvironment, and key signaling pathways. Through an in-depth review of previous studies, we aim to provide a theoretical foundation and strategic guidance to enhance the effectiveness of immunotherapy for PCa and to facilitate the development and translation of more targeted and effective immunotherapeutic interventions.