Here, we demonstrate that (1) NK cells kill melanoma cells with varying efficacy, (2) the killing is predominately mediated via the TRAIL signaling pathway, (3) the expression of PD-L1 by melanoma cell lines lowers their sensitivity for NK cell killing and can be reversed by the inhibition of the PD-L1/PD-1 checkpoint, and (4) IFNβ increases the killing of PD-L1-negative cell lines by NK cells, which can be further augmented by blocking the PD-L1/PD-1 checkpoint induced by IFNβ. Here, TNFSF10 is linked to melanoma.