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...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
April 17, 2026
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| In: |
iScience
Year: 2026, Volume: 29, Issue: 4, Pages: 1-22 |
| ISSN: | 2589-0042 |
| DOI: | 10.1016/j.isci.2026.115492 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.isci.2026.115492 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2589004226008679 
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| Author Notes: | Sebastiano Giorgetta, Francesco Cortopassi, Theodoros Chanis, Jing Ni, Margareta P. Correia, Carsten Sticht, Volker Ast, Michael Platten, Adelheid Cerwenka, and Ana Stojanovic |
| Summary: | 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. |
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| Item Description: | Gesehen am 21.05.2026 |
| Physical Description: | Online Resource |
| ISSN: | 2589-0042 |
| DOI: | 10.1016/j.isci.2026.115492 |