Depletion of CCR8+ Treg cells restores dendritic cell function to drive anti-tumor immunity

CCR8-targeted regulatory T (Treg) cell depletion is a potent strategy to overcome tumor immunosuppression, yet the cellular mechanisms driving the subsequent immune response have remained unclear. This study demonstrates that anti-CCR8 antibody treatment promotes anti-tumor immunity by specifically relieving mature dendritic cells (DCs) enriched in immunoregulatory molecules (mregDCs) from Treg cell-mediated suppression. Using single-cell RNA sequencing and spatial transcriptomics in a murine colon carcinoma model, we revealed that CCR8 + Treg cell depletion induces rapid upregulation of costimulatory and activation signals in intratumoral mregDCs. The treatment also decreased mregDCs proximity to suppressive Treg cells while promoting closer interactions with both CD4 + and CD8 + effector T cells. This reactivation was also evident in tumor-draining lymph nodes, where tumor antigen-bearing migratory DCs—representing the dLN-migrating counterparts of intratumoral mregDCs—exhibited enhanced maturation, accompanied by robust priming of tumor-specific CD8 + T cells. Therapeutic efficacy was dependent on lymphocyte egress, confirming the critical role of peripheral priming. In addition, multiplex immunohistochemistry in human colorectal cancer revealed a preferential spatial association between CCR8 + Treg cells and LAMP3 + DCs (human DCs exhibiting features associated with the mregDC state), supporting the clinical relevance of this axis. Collectively, these findings indicate that anti-CCR8 therapy restores a critical antigen-presentation axis by liberating mregDCs from Treg cell-mediated suppression, thereby re-initiating the cancer-immunity cycle.