Increased CaMKK2 expression is an adaptive response that maintains the fitness of tumor-infiltrating natural killer cells

ABSTRACT Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been considerable interest in developing CaMKK2 inhibitors as potential cancer therapeutics. However, the roles of CaMKK2 in other cellular compartments within the tumor immune environment remain to be established, an impediment to the clinical development of these agents. We report that CaMKK2 is expressed at low basal levels in natural killer (NK) cells but is significantly upregulated in tumor-infiltrating NK cells where it suppresses apoptosis and promotes proliferation. It was further demonstrated that NK cell-intrinsic deletion of CaMKK2 increased metastatic progression across several murine models, establishing a critical role for this enzyme in NK cell tumor immunity. Interestingly, ablation of the CaMKK2 protein, but not inhibition of its kinase activity, resulted in decreased NK cell survival. These results indicate an important scaffold function for CaMKK2 in NK cells and suggest that competitive CaMKK2 inhibitors and ligand-directed degraders (LDDs) are likely to have distinct therapeutic utilities. Finally, we determined that intracellular lactic acid is a key driver of CaMKK2 expression, suggesting that upregulated expression of this enzyme is an adaptive mechanism by which tumor-infiltrating NK cells mitigate the deleterious effects of a lactate-rich tumor environment. The findings of this study should inform strategies to manipulate the CaMKK2 signaling axis as a therapeutic approach in cancer.