Selective Depletion of Tumor-Infiltrating CD4+CCR8+ Tregs by AZ084, a Novel CCR8 Antagonist.

Regulatory T cells (Tregs) are key mediators of immunosuppression in ovarian cancer, yet strategies for selectively targeting tumor-infiltrating Tregs remain limited. CD4+CCR8+ Tregs have been proposed as a highly suppressive subset, but their functional relevance and therapeutic potential require further investigation. Here, we demonstrate that CCR8 is preferentially expressed on tumor-infiltrating CD4+ Tregs in syngeneic ID8 and B16 tumor models, accounting for a significantly higher proportion compared with CD4+ conventional T cells and CD8+ T cells (p < 0.001). Functionally, CD4+CCR8+ Tregs exhibited enhanced suppressive activity, markedly inhibiting IFN-γ production by CD8+ T cells (p < 0.01). The antagonist AZ084 significantly impaired Treg differentiation and alleviated Treg-mediated suppression in vitro (p < 0.01). In vivo, AZ084 treatment effectively suppressed tumor growth in both ovarian cancer and melanoma models (p < 0.01), accompanied by a reduction in tumor-infiltrating CD4+CCR8+ Tregs and an increase in CD8+ T cell infiltration and effector function (p < 0.05). Importantly, AZ084 had minimal impact on splenic immune cell composition (p > 0.05), suggesting limited systemic immunotoxicity. Collectively, our findings identify CCR8 as a selective marker and functional regulator of tumor-infiltrating Tregs. Targeting CCR8 with AZ084 represents a promising strategy to enhance antitumor immunity while preserving peripheral immune homeostasis, providing a potential therapeutic approach for ovarian cancer.