Targeting regulatory T cells in the prostate cancer microenvironment: From mechanisms to therapeutics (Review).

Prostate cancer (PCa) is a heterogeneous cancer. Regulatory T cells (Tregs) within the tumor microenvironment play a pivotal role in promoting immune evasion and disease progression. This review systematically outlines the development, functional characteristics and regulatory networks of Tregs in this environment. Synthesis of recent spatial transcriptomic and single‑cell RNA‑sequencing data revealed that the functional heterogeneity and spatial distribution of Tregs within the tumor stroma, rather than their absolute abundance alone, are critical determinants of immune evasion. For instance, a high stromal density of Tregs is associated with a >2‑fold increased risk of biochemical recurrence, and an activated, highly suppressive Treg subset predominates in high‑Gleason score tumors. The impact of current and emerging therapeutic strategies, including monoclonal antibody‑based and combination immunotherapies, on Treg function, was critically evaluated. The present analysis indicates that while anti‑cytotoxic T‑lymphocyte‑associated protein (CTLA)‑4 monotherapy has failed to show a survival benefit in Phase III trials for metastatic castration‑resistant PCa, fragment crystallizable‑enhanced anti‑CTLA‑4 antibodies achieve up to 50% intratumoral Treg depletion in preclinical models. The rationale for targeting specific Treg subsets was highlighted, such as C‑C motif chemokine receptor 4+ and glycoprotein‑A repetitions predominant+ and integrating Treg‑directed approaches with androgen deprivation therapy (ADT) or radiotherapy to mitigate treatment‑induced Treg expansion (e.g., ADT can increase intratumoral Tregs by 30‑40%). Existing challenges and prospects for the clinical translation of Treg‑targeting approaches were also discussed, emphasizing the need for patient stratification guided by Treg‑related biomarkers.