Natural killer (NK) cells have evolved to detect and kill aberrant cells. NK cell function is governed by the cytokine interleukin (IL)-15 and the detection of foreign and self-ligands, which together generate an integrated intracellular signal cascade. There is a great deal of interest in understanding the inhibitory signals that curb NK cell responses, with the aim of developing new immunotherapies which enhance NK cell detection and killing of cancer cells. The Suppressor of cytokine signalling (SOCS) proteins are induced in response to JAK/STAT activation and act to limit the extent of cytokine receptor signalling. We have identified CIS (Cytokine-inducible SH2-containing protein; Cish gene) as the critical SOCS protein regulating IL-15 signalling in NK cells. Cish was rapidly induced in response to IL-15 and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by superior proliferation, survival, IFN-γ production and cytotoxicity towards tumours. CIS was shown to interact with JAK1, inhibiting JAK1 kinase activity and targeting it for proteasomal degradation. Cish-/- mice were resistant to experimental melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity (Delconte et al., Nat Immunol, 2016). This study uncovered a potent checkpoint in NK cell-mediated tumour immunity.