Sirt6 deficiency-induced senescent NK cell populations are associated with resistance to anti-PD-1 therapy

Loss and dysfunction of natural killer cells have been implicated in tumor progression and immunotherapy resistance. However, the underlying mechanisms remain incompletely known. We define senescence as a hallmark and driving force of NK cell dysfunction in the tumor microenvironment, promoting tumor progression and antiPD-1 resistance in experimental or preclinical mouse tumor models. Using the genetic or pharmacological approach, we demonstrate that Sirt6 deficiency leads to histone hyperacetylation, which activates senescence programming and STAT3 signaling in NK cells, thereby driving anti-PD-1 resistance.