CCR8⁺ regulatory T cell depletion overcomes immune checkpoint blockade resistance in BRCA2-deficient prostate cancer

BRCA2-mutated prostate cancer is an aggressive, genomically unstable subtype, yet how this genomic instability influences tumor immunity remains undefined. We developed an isogenic, immunocompetent model of Brca2-deficient prostate cancer in which BRCA2 loss activated the cGAS/STING pathway and a type I interferon response across multiple cellular compartments, paradoxically leading to an overall immunosuppressed tumor microenvironment. Within this microenvironment, tumor-associated macrophages were interferon-responsive and expressed the CCR8 ligand Ccl8, and there was enrichment of immunosuppressive CCR8 regulatory T cells (Treg). Anti-PD-1 monotherapy was ineffective and instead reinforced this immunosuppressive circuit, leading to expansion of CCR8 Tregs. However, depletion of CCR8 regulatory T cells overcame resistance to checkpoint blockade. Analysis of human BRCA2-mutated prostate cancer showed elevated CCR8 expression, supporting the translational relevance of the CCR8 Treg axis as a potential therapeutic target in a disease largely refractory to immunotherapy.