Impact of immunotherapy as a monotherapy or in combination with conventional therapies on regulatory T-cell (Treg) modulation in prostate cancer: a systematic review

BACKGROUND: Prostate cancer is known to have a cold tumor microenvironment (TME) that promotes immune evasion through different cellular pathways. Aggressive disease progression is often linked to Regulatory T cells (Tregs) which play an important role in immunosuppression. While immunotherapy aims to use the immune system to fight tumor cells, its efficacy is frequently hindered by Tregs, which prevent effector T cells from reaching and fighting tumor cells. This review evaluates the impact of different immunotherapeutic interventions, alone or in combination, on Treg frequency and function within the prostate TME. METHODS: Following PRISMA guidelines, a systematic search of major databases identified studies investigating immunotherapeutic effects on Tregs in prostate cancer. Studies were included if they evaluated monotherapies or combination strategies, as defined by inclusion criteria. RESULTS: 31 studies met the inclusion criteria. Qualitative analysis revealed that monotherapies, including immune checkpoint inhibitors and vaccines, produced inconsistent effects on Treg populations, which in many cases did not significantly decrease their levels or suppressive function. Notable exceptions included targeted recruitment inhibitors such as anti-CCR4 and specific viral-mediated therapies. In contrast, combination therapies proved to be more effective in reshaping the TME. When immunotherapy and other treatment such as androgen deprivation therapy, immunogenic chemotherapy, and targeted molecular inhibition are combined, enhanced anti-tumor immunity is observed. CONCLUSION: Successful modulation of the prostate TME requires shifting from monotherapy toward combination strategies that overcome Treg-mediated immunosuppression. Effector-to-Treg ratios and functional markers, rather than Treg frequency alone, may better predict outcomes, as CD8⁺ infiltration does not always reflect restored cytotoxicity. These findings highlight the dual potential of Tregs as therapeutic targets and biomarkers in prostate cancer.