Single-Cell RNA Sequencing of Tumor-Infiltrating NK Cells Reveals that Inhibition of Transcription Factor HIF-1α Unleashes NK Cell Activity

Immunity. 2020 Jun 16;52(6):1075-1087.e8. doi: 10.1016/j.immuni.2020.05.001. Epub 2020 May 22.


Enhancing immune cell functions in tumors remains a major challenge in cancer immunotherapy. Hypoxia is a common feature of solid tumors, and cells adapt by upregulating the transcription factor HIF-1α. Here, we defined the transcriptional landscape of mouse tumor-infiltrating natural killer (NK) cells by using single-cell RNA sequencing. Conditional deletion of Hif1a in NK cells resulted in reduced tumor growth, elevated expression of activation markers, effector molecules, and an enriched NF-κB pathway in tumor-infiltrating NK cells. Interleukin-18 (IL-18) from myeloid cells was required for NF-κB activation and the enhanced anti-tumor activity of Hif1a-/- NK cells. Extended culture with an HIF-1α inhibitor increased human NK cell responses. Low HIF1A expression was associated with high expression of IFNG in human tumor-infiltrating NK cells, and an enriched NK-IL18-IFNG signature in solid tumors correlated with increased overall patient survival. Thus, inhibition of HIF-1α unleashes NK cell anti-tumor activity and could be exploited for cancer therapy.

Keywords: HIF-1α; IFN-γ; IL-18; NF-κB; NK cells; natural killer cells; single-cell RNA sequencing; tumor immunology; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Computational Biology
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Mice
  • Mice, Knockout
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / mortality
  • Prognosis
  • Single-Cell Analysis
  • Transcriptome
  • Tumor Microenvironment / immunology


  • Biomarkers
  • Cytokines
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit