Immune checkpoint blockade therapy (ICT) is effective against tumors, but resistance due to regulatory T cell (Treg) infiltration poses challenges. Targeting CCR8, predominantly expressed on tumor Tregs, with human antibodies offers a promising therapeutic approach. Three fully human monoclonal antibodies targeting CCR8 were developed and characterized in CCR8 knock-out RenMabTM mice. These antibodies recognize a unique epitope, bind to both human and mouse CCR8 proteins, inhibit calcium flux induced by CCL1, and demonstrate potent anti-tumor activity in vivo. These findings suggest that these antibodies are promising candidates for further drug development.