ASK1 suppresses NK cell-mediated intravascular tumor cell clearance in lung metastasis

Cancer Sci. 2021 Apr;112(4):1633-1643. doi: 10.1111/cas.14842. Epub 2021 Mar 6.


Tumor metastasis is the leading cause of death worldwide and involves an extremely complex process composed of multiple steps. Our previous study demonstrated that apoptosis signal-regulating kinase 1 (ASK1) deficiency in mice attenuates tumor metastasis in an experimental lung metastasis model. However, the steps of tumor metastasis regulated by ASK1 remain unclear. Here, we showed that ASK1 deficiency in mice promotes natural killer (NK) cell-mediated intravascular tumor cell clearance in the initial hours of metastasis. In response to tumor inoculation, ASK1 deficiency upregulated immune response-related genes, including interferon-gamma (IFNγ). We also revealed that NK cells are required for these anti-metastatic phenotypes. ASK1 deficiency augmented cytokine production chemoattractive to NK cells possibly through induction of the ligand for NKG2D, a key activating receptor of NK cells, leading to further recruitment of NK cells into the lung. These results indicate that ASK1 negatively regulates NK cell-dependent anti-tumor immunity and that ASK1-targeted therapy can provide a new tool for cancer immunotherapy to overcome tumor metastasis.

Keywords: ASK1; NK cell; NKG2D; intravascular tumor cell clearance; lung metastasis.

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Female
  • HEK293 Cells
  • Humans
  • Immunotherapy / methods
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Lung / immunology
  • Lung / metabolism
  • Lung / pathology
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis / immunology
  • Neoplasm Metastasis / pathology*
  • RAW 264.7 Cells


  • Interferon-gamma
  • MAP Kinase Kinase Kinase 5
  • Map3k5 protein, mouse