CD96. a member of the immunoglobulin superfamily, is a transmembrane glycoprotein expressed primarily on natural killer (NK) cells and subsets of T cells. It shares structural homology with other immune regulators like DNAM-1 and TIGIT, forming a network of receptors that modulate immune synapse interactions. CD96 binds to CD155 (PVR), a ligand overexpressed on many cancer cells and infected cells, though its functional role remains context-dependent. Initially identified as a potential activator of lymphocyte adhesion, subsequent studies revealed its dual role in immune regulation. In tumor microenvironments, CD96 is implicated in immune suppression, where its engagement with CD155 may dampen NK cell cytotoxicity, promoting immune evasion. Conversely, in viral infections or inflammatory settings, CD96 may enhance immune cell recruitment and effector functions.
Therapeutic interest in CD96 antibodies stems from its potential as a checkpoint inhibitor target. Preclinical studies suggest that blocking CD96-CD155 interactions can restore NK cell-mediated antitumor responses, particularly in combination with PD-1/PD-L1 inhibitors. However, conflicting data exist regarding its precise signaling mechanisms, with evidence pointing to both inhibitory and costimulatory pathways depending on cellular context. Current research focuses on optimizing anti-CD96 antibody specificity and evaluating its efficacy in clinical trials, aiming to exploit its regulatory role in cancer immunotherapy. Further exploration of its biology is needed to clarify its therapeutic potential and avoid unintended immune modulation.