Harnessing adaptive natural killer cells in cancer immunotherapy

•Recent insights into the functional plasticity of human NK cells are discussed.•Guided differentiation and selective expansion hold promises for more specific NK cell therapy.•Manipulation of metabolic pathways may rescue the functional potential of NK cells during in vitro expansion.

Natural killer (NK) cells are innate lymphocytes with a refined ability to recognize transformed cells through a broad array of activating receptors in combination with stochastically expressed inhibitory receptors that recognize MHC-class I. Recent advances in NK cell biology have revealed a high degree of functional plasticity that can be attributed to dynamic cell-to-cell interactions in concert with transcriptional and epigenetic reprogramming. Here, we discuss how new insights into the adaptive behavior of NK cells pave the way for next generation cell therapy based on guided differentiation and selective expansion of particularly cytotoxic NK cell subsets.