CD161, also known as KLRB1 or NKRP1A, is a C-type lectin-like receptor primarily expressed on the surface of natural killer (NK) cells and a subset of T cells, including mucosal-associated invariant T (MAIT) cells and some CD8+ T cells. It is particularly enriched in immune cells located in mucosal sites such as the gut and liver. CD161 binds to its ligand, lectin-like transcript 1 (LLT1, also known as CLEC2D), and this interaction can have both inhibitory and costimulatory effects on immune cells. In the context of cancer immunotherapy, CD161 has been identified as a potential inhibitory receptor in glioma-infiltrating T cells. Its activation by CLEC2D on tumor or immunosuppressive cells can dampen T cell responses against cancer cells. Recent studies suggest that blocking the CD161-CLEC2D interaction may enhance T cell-mediated antitumor activity, making CD161 a promising target for cancer immunotherapy.