Hepatic iNKT cells facilitate colorectal cancer metastasis by inducing a fibrotic niche in the liver

  • iScience. 2025 Apr 6;28(5):112364. doi: 10.1016/j.isci.2025.112364.
Marc Nater  1 ,  Michael Brügger  2 ,  Virginia Cecconi  1 ,  Paulo Pereira  1 ,  Geo Forni  1 ,  Hakan Köksal  1 ,  Despoina Dimakou  1 ,  Michael Herbst  1 ,  Anna Laura Calvanese  1 ,  Giulia Lucchiari  1 ,  Christoph Schneider  3 ,  Tomas Valenta  2 ,  Maries van den Broek  1
Affiliations
  • 1. Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
  • 2. Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
  • 3. Institute of Physiology, University of Zurich, Zurich, Switzerland.
PMID: 40292307 DOI: 10.1016/j.isci.2025.112364
Abstract

The liver is an important metastatic organ that contains many innate immune cells, yet little is known about their role in anti-metastatic defense. We investigated how invariant natural killer T (iNKT) cells influence colorectal cancer-derived liver metastasis using different models in immunocompetent mice. We found that hepatic iNKT cells promote metastasis by creating a supportive niche for disseminated Cancer cells. Mechanistically, iNKT cells respond to disseminating Cancer cells by producing the fibrogenic cytokines interleukin-4 (IL-4) and IL-13 in a T cell receptor-independent manner. Selective abrogation of IL-4 and IL-13 sensing in hepatic stellate cells prevented their transdifferentiation into extracellular matrix-producing myofibroblasts, which hindered metastatic outgrowth of disseminated Cancer cells. This study highlights a novel tumor-promoting axis driven by iNKT cells in the initial stages of metastasis.

Keywords
Biological sciences; Immune response; Immunology; Microenvironment; Natural sciences.
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