CLEC2D is a C-type lectin receptor that functions as an inhibitory ligand for the CD161 receptor (encoded by KLRB1) on immune cells. Functionally, CLEC2D protects target cells from natural killer cell-mediated cytotoxicity by engaging CD161 on T cells and NK cells, thereby dampening their anti-tumor activity 1. The receptor-ligand pair CLEC2D-KLRB1 represents a critical immune checkpoint in cancer immunity; elevated CLEC2D/KLRB1 ratio correlates with advancing cancer stages and poor survival outcomes across multiple cancer types 2. CLEC2D is highly expressed in hematological malignancies and by tumor-infiltrating myeloid cells in solid tumors 3. Blocking CD161-CLEC2D interactions enhances T cell cytotoxicity, cytokine production, and proliferation against lymphomas and leukemias, with survival benefits demonstrated in humanized mouse models 3. In HPV-positive oropharyngeal cancers, elevated CD161 expression on tumor-resident memory T cells associates with dampened anti-tumor activity and reduced immunotherapy efficacy 4. Notably, CD161+ T cells and CLEC2D-expressing B cells were identified as immune evasion mechanisms in relapsed/refractory angioimmunoblastic T-cell lymphoma 5. Clinically, CLEC2D blockade via anti-CD161 monoclonal antibodies represents a promising immunotherapeutic strategy. Additionally, forced CLEC2D expression, combined with CD58 loss, mitigates NK cell rejection of allogeneic CAR-T cells in immunotherapy 6.