Dysfunctional natural killer cells can be reprogrammed to regain anti-tumor activity

Natural killer (NK) cells are critical to the innate immune system, as they recognize antigens without prior sensitization, and contribute to the control and clearance of viral infections and cancer. However, a significant proportion of NK cells in mice and humans do not express classical inhibitory receptors during their education process and are rendered naturally "anergic", i.e., exhibiting reduced effector functions. The molecular events leading to NK cell anergy as well as their relation to those underlying NK cell exhaustion that arises from overstimulation in chronic conditions, remain unknown. Here, we characterize the "anergic" phenotype and demonstrate functional, transcriptional, and phenotypic similarities to the "exhausted" state in tumor-infiltrating NK cells. Furthermore, we identify zinc finger transcription factor Egr2 and diacylglycerol kinase DGK alpha as common negative regulators controlling NK cell dysfunction. Finally, experiments in a 3D organotypic spheroid culture model and an in vivo tumor model suggest that a nanoparticle-based delivery platform can reprogram these dysfunctional natural killer cell populations in their native microenvironment. This approach may become clinically relevant for the development of novel anti-tumor immunotherapeutic strategies. The mechanisms underlying naturally occurring "anergic" and overstimulation-induced "exhausted" states of natural killer (NK) cells remain unclear. This study identifies common functional and phenotypic characteristics of these two dysfunctional states, and identifies common regulators that can be targeted to reprogram dysfunctional NK cells.The transcription factor Egr2 and diacylglycerol kinase DGK alpha regulate both dysfunctional states of NK cells. Egr2 silencing rescues anergic NK cell cytotoxicity via the EGR2-DGK alpha-MAPK-pERK axis, potentially modulating SHP-1 activity and calcium levels. Naturally occurring anergic NK cells have functional, transcriptional, and phenotypic similarities to exhausted NK cells within the tumor microenvironment. A nanoparticle-based method can reprogram dysfunctional NK cells in their native milieu and increase their anti-tumor activity. Common intrinsic regulators of dysfunctional "anergic" and "exhausted" NK cells can be targeted to restore cytotoxicity.