Killer cell immunoglobulin-like receptor 3DL3 (KIR3DL3) is a member of the killer cell Ig-like (KIR) receptor family. When KIR3DL3 is expressed on T and natural killer (NK) cells in the tumor microenvironment, it suppresses immune responses following engagement with HHLA2, suggesting that the KIR3DL3-HHLA2 axis potentially represents a novel immune checkpoint pathway and that blockade of KIR3DL3 signaling could promote antitumor immunity.