Cytotoxic T lymphocytes such as T and NK cells are critically involved in the immune response to cancer development. Their cell-surface receptors coordinate to precisely regulate their function, and dysregulation of these molecules has been linked to immune escape. A recent study identified molecules targeting one of these receptors: T cell immunoglobulin and ITIM domain (TIGIT). TIGIT is a novel immune checkpoint molecule involved in T and NK cell anergy. Binding with its ligand, PVR, can induce immune tolerance, allowing cancer cells to escape immune surveillance. To facilitate the design of inhibitors targeting TIGIT/PVR binding, researchers examined the binding interaction in silico. Their results suggested that the loops of PVR undergo a major rearrangement upon binding to TIGIT. The potential residues critical for the TIGIT/PVR interaction were discovered, and simulation analysis identified four PVR mutants with enhanced affinity to TIGIT. This computational analysis provides new insights into the TIGIT/PVR interaction and identifies mutant PVR molecules with the potential to serve as immunotherapy candidates to block this interaction and inhibit immune escape.