The PVR-TIGIT/CD96/CD226 axis: a novel immune checkpoint target in ovarian cancer.

The poliovirus receptor (CD155) is an emerging immune checkpoint molecule involved in the suppression of anti-tumor immunity. In ovarian cancer, CD155 is frequently overexpressed and interacts with receptors such as TIGIT, CD96, and CD226 to modulate the activity of T cells, NK cells, and dendritic cells. These interactions contribute to immune cell exhaustion, regulatory T cell expansion, and impaired cytotoxic responses, facilitating tumor immune evasion. Recent studies have revealed that CD155 expression is influenced by tumor metabolism, autophagy, and cytokine signaling. Therapeutic strategies targeting the CD155 axis-through monoclonal antibodies, bispecific constructs, or engineered T/NK cells-are being actively explored and show promise in enhancing anti-tumor responses, particularly when combined with existing checkpoint inhibitors. This review provides a comprehensive overview of the structure, function, and receptor interactions of CD155 (PVR), with a particular focus on its immunoregulatory role in the ovarian tumor microenvironment. We discuss the signaling mechanisms of the TIGIT/CD96/CD226 axis, its impact on diverse immune cell populations, and the current landscape of therapeutic strategies targeting this pathway. Finally, we evaluate the potential of CD155 and its receptors as predictive biomarkers and therapeutic targets to overcome immune resistance and improve outcomes in ovarian cancer.