CD96, a type I transmembrane glycoprotein belonging to the immunoglobulin superfamily, is mainly expressed by cells of hematopoietic origin, especially T and NK cells [4]. It interacts with CD155 on target cells and is involved in regulating immune responses. CD96, along with CD226 and TIGIT, forms an immune regulatory network that fine-tunes the immune response through shared ligands and differential receptor-ligand affinities [3,5,6].

In cancer, CD96 has been extensively studied. In breast cancer, tumor cell-intrinsic CD96 enhances chemoresistance and cancer stemness by promoting mitochondrial fatty acid β-oxidation via the CD155-CD96-Src-Stat3-Opa1 pathway [1]. In cervical cancer, CD96 expression is elevated on CD8+ tumor-infiltrating lymphocytes (TILs) from patients insensitive to PD-1 blockade. Blocking CD96 can enhance the effect of PD-1 blockade, improving the function of CD8+ TILs [2]. Cd96-/-mice display hypersensitive NK-cell responses to immune challenge and significant tumor resistance, indicating its inhibitory role in immune function [6]. In giant cell arteritis, a defective CD155-CD96 immune checkpoint leads to abnormal T-cell differentiation and IL-9 production [7].

In conclusion, CD96 is a crucial immune regulator. Its role in cancer immunotherapy and autoimmune diseases has been revealed through in vivo studies, especially gene knockout mouse models. These models help us understand how CD96 affects immune cell function and disease progression, providing potential targets for treating cancer and autoimmune diseases.