Functional segregation of HIF-1α and AhR controls NK cell responsiveness under hypoxia

Multiple mechanisms operate to transform microenvironmental information into cellular adaptation, but how environmental sensors mechanistically synergize to fine-tune natural killer (NK) cell functions is underexplored. Although the deletion of HIF-1α, the sensor for hypoxia, was shown to impact NK cell responses, we here demonstrate that hypoxia-inflicted adaptations in NK cells are differentially hard-wired through HIF-1α. The hypoxia-HIF-1α axis repressed NK cell oxidative metabolism and the response to IL-12/18 through transcription. However, the IL-12/18-induced IFN-γ production was preserved under hypoxia. This was attributed to the activation of the aryl-hydrocarbon receptor (AhR) that magnified the engagement of the cMyc-mTORC1-IκBζ pathway, resulting in elevated IFN-γ expression. NK cells harmonized AhR/HIF-1α-mediated signals through defined transcriptional modules, also detected in similar microenvironments, such as in solid tumors. Together, NK cell functions are fine-tuned through regulatory networks controlled by environmental sensors, which act as superordinate checkpoints for NK cell outputs.