CD96 is a type I transmembrane glycoprotein of the immunoglobulin superfamily expressed primarily on T and NK cells 1. It functions as an inhibitory immune checkpoint receptor that engages with CD155 (PVR) on target cells to suppress immune responses 12. CD96 operates within a regulatory network alongside CD226 and TIGIT that fine-tunes immune responses through shared ligands and differential receptor affinities 2. Mechanistically, CD96 mediates NK cell and CD8+ T cell inhibition upon CD155 binding 3. In the tumor microenvironment, CD96 expression is elevated on exhausted CD8+ tumor-infiltrating lymphocytes, particularly those coexpressing PD-1, and promotes a terminally exhausted phenotype 3. CD96 blockade enhances CD8+ T cell function and synergizes with PD-1 blockade to improve anti-tumor immunity 34. Notably, CD155-TIGIT interactions—not CD155-CD96—mediate primary NK cell evasion by circulating tumor cells, suggesting context-dependent roles 5. Clinically, elevated CD96 expression correlates with poor prognosis and immunotherapy resistance in cervical and breast cancers 36. Beyond immune cells, tumor cell-intrinsic CD96 promotes chemoresistance and cancer stemness through mitochondrial fatty acid β-oxidation 6. CD96 represents a promising therapeutic target for combination checkpoint blockade strategies 347.