CD226 is a costimulatory immunoglobulin superfamily receptor predominantly expressed on natural killer (NK) cells and cytotoxic T cells that plays a critical role in immune surveillance and cytotoxicity 1. Upon binding its ligands CD155 (PVR) or CD112 (NECTIN2) on target cells, CD226 promotes cytotoxic activity through Src kinase-mediated phosphorylation, enabling GRB2 adapter binding and downstream activation of VAV1, PI3K, and ERK/AKT kinases 2. CD226 functions as a dominant costimulatory receptor whose signaling can be antagonized by coinhibitory receptors: PD-1 inhibits CD226 phosphorylation via its ITIM domain, while TIGIT blocks CD226 engagement with shared ligand PVR 23. Clinically, CD226 expression on infiltrating CD8+ T cells associates with therapeutic benefit in non-small cell lung carcinoma patients receiving anti-PD-L1 therapy 2. CD226 dysregulation contributes to multiple immune-mediated diseases: genetic polymorphisms associate with primary biliary cholangitis susceptibility 4, while reduced CD226 expression on intratumoral CD8+ T cells correlates with checkpoint inhibitor resistance in cervical cancer 5. In type 1 diabetes, CD226+CD8+ T cells serve as biomarkers for β-cell function decline 6. CD226 emerges as a promising therapeutic target for enhancing anti-tumor immunity and treating autoimmune diseases.