CCR8 is a key chemokine receptor primarily expressed on regulatory T cells (Tregs) infiltrating the tumor microenvironment. It plays a decisive role in mediating immunosuppression by facilitating Treg recruitment and activation. Emerging research highlights the interaction between CCR8 and glycosaminoglycans (GAGs), which serve as essential co-receptors. GAGs facilitate the presentation of ligands like CCL1 to CCR8, effectively concentrating chemokines on the cell surface to enhance signaling efficiency. Targeting the CCR8-GAG axis represents a sophisticated strategy for selective Treg depletion, offering high precision for cancer immunotherapy while minimizing systemic autoimmune side effects.