Viral escape from NK-cell-mediated immunosurveillance: A lesson for cancer immunotherapy?

Natural killer (NK) cells are innate lymphocytes that participate in immune responses against virus-infected cells and tumors. As a countermeasure, viruses and tumors employ strategies to evade NK-cell-mediated immunosurveillance. In this review, we examine immune evasion strategies employed by viruses, focusing on examples from human CMV and severe acute respiratory syndrome coronavirus 2. We explore selected viral evasion mechanisms categorized into three classes: (1) providing ligands for the inhibitory receptor NKG2A, (2) downregulating ligands for the activating receptor NKG2D, and (3) inducing the immunosuppressive cytokine transforming growth factor (TGF)-β. For each class, we draw parallels between immune evasion by viruses and tumors, reviewing potential opportunities for overcoming evasion in cancer therapy. We suggest that in-depth investigations of host–pathogen interactions between viruses and NK cells will not only deepen our understanding of viral immune evasion but also shed light on how NK cells counter such evasion attempts. Thus, due to the parallels of immune evasion by viruses and tumors, we propose that insights gained from antiviral NK-cell responses may serve as valuable lessons that can be leveraged for designing future cancer immunotherapies.