Disarming the natural killers: mechanisms of NK cell dysfunction in hematological malignancies

Natural Killer (NK) cells are innate lymphocytes that provide rapid first-line defense against infected and transformed cells through receptor-mediated recognition of stress-induced ligands. Unlike adaptive lymphocytes, NK cells act without prior sensitization, and allogeneic NK cells are generally well-tolerated, making them attractive candidates for off-the-shelf cell-based immunotherapies, particularly in hematological malignancies. However, NK cell function in hematological malignancies is frequently impaired. Mechanisms of suppression include disrupted differentiation, metabolic reprogramming and impaired cytotoxic and antigen-recognition capabilities. The tumor and bone marrow microenvironment contribute to these defects through hypoxia, nutrient deprivation and accumulation of immunosuppressive metabolites such as adenosine. In addition, inhibitory cytokines and immune checkpoint–mediated cell-cell interactions further restrain NK cell activity. Understanding the receptor-ligand interactions that govern NK cell cytotoxicity, and the microenvironmental and cellular factors that repress NK cell function, is critical to overcoming these barriers. This review synthesizes current knowledge on NK cell cytotoxic mechanisms, surface receptors mediating target recognition and the multifaceted suppression observed in hematological malignancies. We describe the metabolic and immunological milieu that limits NK cell activity, which can highlight potential targets for improving NK cell persistence, infiltration, and therapeutic efficacy.