Immunotherapeutic strategies targeting the PVR–TIGIT/CD96/CD226 signaling pathway in glioma treatment

Background To summarise the molecular interactions of Poliovirus Receptor (PVR) with its receptors (inhibitory TIGIT/CD96 and activating CD226), to delineate how these interactions drive glioma immune escape, and to evaluate emerging PVR-directed therapeutic strategies.Methods Critical synthesis of pre-clinical and clinical data (to 2025) on PVR pathway biology and drug development in glioma.Results PVR ligation of TIGIT/CD96 suppresses T- and NK-cell cytotoxicity, skews cytokine profiles toward regulatory phenotypes, and blunts tumour cell death; concurrent CD226 engagement is competitively antagonised, amplifying immune escape. Elevated PVR expression correlates with reduced effector infiltration, increased Treg and exhausted T-cell signatures, and inferior patient prognosis. PVR blockade via monoclonal antibodies (e.g. anti-TIGIT/CD96), bispecific engagers, and CAR-modified T/NK cells restores anti-tumour immunity in pre-clinical glioma models, with early-phase trials underway.Conclusions The PVR–TIGIT/CD96/CD226 axis is a critical immune checkpoint in glioma. Targeted disruption of this pathway offers a promising strategy to overcome resistance and improve clinical outcomes.