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.