Regulatory T cells in ovarian cancer

The paradox of immune resistance in High-Grade Serous Carcinoma (HGSC) of the ovary, despite high immune cell infiltration, is caused by a complex, multi-layered immunosuppressive tumor microenvironment (TME) that disables and excludes effector immune cells. This is resolved by the aggressive co-option of immunosuppressive networks, chief among which are Regulatory T cells (Tregs). Defined by the expression of the CD4 surface marker and the master transcription factor FoxP3, Tregs maintain immune homeostasis but are exploited by OC to promote tumor progression and immune evasion. Since CD4 + CD25+ regulatory lineage was discovered in nineties the three-decade of Treg research in OC has proved that tumor-infiltrating Tregs reduce whereas CD8 + cells increase survival. CD8+/Treg ratio is thus established as a powerful prognostic index of OC. Mechanistic dissection revealed the TME’s sophisticated redundancy, highlighting chemokine-mediated trafficking via the CCL22/CCR4 axis, cytokine-driven induction and proliferation (e.g., TGF-beta and IL-6/TNFR2 signalling) and metabolic manipulation as core enabling factors. Contemporary translational efforts are defined by the shift away from non-selective strategies, such as metronomic chemotherapy, toward precision immunotherapy. Current trials focus on selective depletion via anti-CCR4 antibodies (Mogamulizumab) or targeted agents (E7777), alongside the strategic use of immune checkpoint inhibitors like CTLA-4 blockers to simultaneously disrupt Treg function and reinvigorate exhausted effector T cells. The increasing phenotypic precision, recognizing functionally distinct subsets like the prognostically favorable exhausted CD4 + T cell population, underscores the current trajectory toward effective, combined immunotherapeutic approaches that aim to decisively shift the suppressive balance within the OC TME.