KLRB1 (CD161) is an inhibitory receptor expressed on natural killer cells and T cell subsets that plays a critical regulatory role in immune surveillance. The receptor functions as a lectin binding carbohydrate epitopes and acts as a ligand for CLEC2D/LLT1 1. Upon activation, KLRB1 stimulates acid sphingomyelinase and elevates intracellular ceramide while promoting AKT1 and RSK1 kinase activation, ultimately suppressing cytotoxic T cell function and interferon-gamma secretion 1. In cancer contexts, KLRB1 expression correlates with immune evasion mechanisms. CD8+ T cells overexpressing KLRB1 in hepatocellular carcinoma exhibit reduced cytotoxicity and are associated with worse prognosis 2. Similarly, glioma-infiltrating T cells expressing KLRB1 display an innate-like low cytotoxic state, and blockade of CD161 enhances T cell-mediated tumor killing both in vitro and in vivo 1. KLRB1 acts as an independent prognostic factor in glioma, enriched in high-grade and IDH-wildtype tumors where it promotes T cell dysfunction 3. Beyond malignancy, KLRB1 marks T cell populations in autoimmune conditions. Memory CD4+ T cells in palmoplantar pustulosis patients exhibit TH17/TH2 plasticity marked by KLRB1/CD161 and GATA3 co-expression 4. Pan-cancer analysis reveals KLRB1 as a prognostic biomarker with high expression predicting better outcomes in most cancers and correlating with improved immunotherapy response 5.