HHLA-2 (B7H7) is a member of the B7 family of ligands and mediates both co-stimulatory (via TMIGD2/CD28H receptor) and inhibitory effects on T cells following antigen recognition. Using a soluble HHLA2-Fc receptor screen we identified KIR3DL3 as a novel inhibitory receptor expressed in activated T and NK cells. Given the high expression of HHLA2 in PD-L1 negative tumors we postulated that the inhibition of the HHLA2/KIR3DL3 checkpoint axis would be beneficial in patients who are refractory to PD-1 immunotherapy (primary or acquired resistance).  The discovery and development of checkpoint inhibitor antibodies targeting the HHLA2/KIR3DL3 axis as cancer immunotherapy activating T and NK cells for targeting PD-1 refractory patients would be discussed.