Natural killers or natural regulators? Dual roles of NK cells in checkpoint immunotherapy

Natural killer (NK) cells have long been recognized as central antitumor effectors capable of eliminating transformed cells without prior sensitization. However, recent studies reveal a more nuanced reality: NK cells can also act as regulators that hinder CD8⁺ T-cell immunity and blunt the efficacy of immune checkpoint blockade (ICB). Two back-to-back in Cancer Discovery provide compelling mechanistic insights. Pozniak et al. demonstrate that cytotoxic NK cells accumulate in immune-excluded melanoma, where they are recruited via CX3CR1 and prevent CD8⁺ T-cell infiltration, thereby limiting responses to anti-PD-1 therapy. In parallel, Song et al. show that (TANKs) cells compete with CD8⁺ T cells for IL-2 and type I interferons (IFN-I; mainly IFN-α/β), disrupting effector differentiation and reducing ICB sensitivity. Collectively, these findings underscore the dual nature of NK cells as both killers and regulators whose context-dependent activity can either amplify or suppress antitumor immunity. Therapeutically, strategies to deplete, block, or reprogram suppressive NK subsets while preserving their cytotoxic and dendritic cell (DC)-recruiting functions may help overcome resistance and enhance the durability of checkpoint blockade.