Journal Article

DKFZ-2026-00886

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Functional segregation of HIF-1α and AhR controls NK cell responsiveness under hypoxia

Giorgetta, S. ; Cortopassi, F. ; Chanis, T. ; Ni, J. ; Correia, M. P. ; Sticht, C. ; Ast, V. ; Platten, M.DKFZ* ; Cerwenka, A. ; Stojanovic, A.

2026
Elsevier St. Louis

Abstract: Multiple mechanisms operate to transform microenvironmental information into cellular adaptation, but howenvironmental 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 throughHIF-1α. The hypoxia-HIF-1α axis repressed NK cell oxidative metabolism and the response to IL-12/18through transcription. However, the IL-12/18-induced IFN-γ production was preserved under hypoxia. Thiswas attributed to the activation of the aryl-hydrocarbon receptor (AhR) that magnified the engagement ofthe cMyc-mTORC1-IκBζ pathway, resulting in elevated IFN-γ expression. NK cells harmonized AhR/HIF1α-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 controlledby environmental sensors, which act as superordinate checkpoints for NK cell outputs.

Note: #DKTKZFB26#

---

Contributing Institute(s):

1. KKE Neuroimmunologie und Hirntumorimmunologie (D170)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2026

---

Database coverage:
; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---