ABSTRACT: FOXP3+ Regulatory T cells (Tregs) play a critical role in mediating tolerance to self-antigens and can repress antitumor immunity through multiple mechanisms. Therefore, targeted depletion of tumor resident Tregs is warranted to promote effective antitumor immunity while preserving peripheral homeostasis. Here we propose the chemokine receptor CCR8 as one such optimal tumor Treg target. CCR8 was expressed by Tregs in both murine and human tumors, and unlike CCR4, a Treg depletion target in the clinic, CCR8 was selectively expressed on suppressive tumor Tregs and minimally expressed on proinflammatory effector T cells (Teffs). Preclinical mouse tumor modeling showed that depletion of CCR8+ Tregs through an FcyR engaging anti-CCR8 antibody, but not blockade, enabled dose-dependent, effective, and long-lasting antitumor immunity that synergized with PD-1 blockade. This depletion was tumor Treg-restricted, sparing CCR8+ T cells in the spleen, thymus, and skin of mice. Importantly, Fc-optimized, non-fucosylated (nf) anti-human CCR8 antibodies specifically depleted Tregs and not Teffs in ex vivo tumor cultures from primary human specimens. These findings suggest that anti-CCR8-nf antibodies may deliver optimal tumor-targeted Treg depletion in the clinic, providing long term antitumor memory responses while limiting peripheral toxicities.