The immune checkpoint protein, CD112 receptor (CD112R, also known as PVRIG), suppresses T and natural killer (NK) cell activation upon binding to tumor-expressed CD112 (Nectin-2) ligands. Here, we determine the structure of the CD112-CD112R complex and use it to guide the engineering of multiple CD112-targeting immunotherapy candidates. The 2.2 Å-resolution crystal structure reveals an antiparallel, lock-and-key binding mode in which CD112R disrupts CD112 homodimerization. Structural analysis informed directed evolution campaigns focused on remodeling the CD112-CD112R interface, resulting in the isolation of CD112R mutants with greatly increased expression and CD112-binding affinity. The highest-affinity variant, CD112R, potently inhibits CD112-CD112R interactions when utilized as a soluble CD112 trap. Furthermore, incorporating CD112R variants into chimeric antigen receptors (CARs) and T cell engagers (TCEs) leads to more robust T cell activation and killing of CD112 triple-negative breast cancer (TNBC) cells compared with wild-type CD112R. This strategy demonstrates how structural insights can be leveraged to efficiently generate panels of "affinity-tuned" biologics for immunotherapy.