NK-cell activation by exogenous miRNAs depends on TLR1. Specific miRNA sequences, including miR-122 and miR-15b, act in a TLR1-dependent fashion to induce nuclear factor-κB signals in human NK cells. This signal works in concert with IL-12 (canonically signaling via STAT4) to induce NK-cell activation. miRNA–TLR1-based NK-cell coactivation results in increased CD69 surface expression, augmented IFN-γ secretion, and enhanced lymphoma cell line control in mice in vivo.