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

Batel Sabag, Abhishek Puthenveetil, Moria Levy, Noah Joseph, Tirtza Doniger, Orly Yaron, Sarit Karako-Lampert, Itay Lazar, Fatima Awwad, Shahar Ashkenazi, Mira Barda-Saad

Research output: Contribution to journalArticlepeer-review


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 DGKα 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.

Original languageEnglish
JournalEMBO Journal
Early online date18 Apr 2024
StateE-pub ahead of print - 18 Apr 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.


  • DGKα
  • Egr2
  • Molecular Mechanisms of NK Cell Dysfunction
  • NK Cell Anergy
  • NK Cell Immunotherapy


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