CD161-blocking antibodies promote cytotoxic lymphocyte function. (A) NK cells, CD4⁺ T cells, and CD8⁺ T cells can express CD161, and upon binding with its ligand CLEC2D, CD161 inhibits lymphocyte activation against malignant cells. (B) A fully human, high-affinity CD161-blocking antibody developed by Alvarez Calderon et al disrupts the interaction between CD161 and CLEC2D. This results in enhanced NK cell– and T cell–mediated cytotoxicity against malignant B cells, as well as increased T-cell cytokine production, proliferation, and tumor infiltration.