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Triple-Negative Breast Cancer Cells Resist Natural Killer Cell-Mediated Killing Through Interleukin-11

Hongmei Yang1, Hao Jia1, Renfei Wu1

  • 1Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, 999078, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|November 3, 2025
PubMed

Insights

Triple-negative breast cancer (TNBC) cells resist natural killer (NK) cell attacks by secreting interleukin-11 (IL-11). This IL-11 pathway inhibits NK cell function, promoting immune evasion. Targeting IL-11 may improve NK cell therapies for TNBC.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Natural killer (NK) cell immunotherapies offer promise for triple-negative breast cancer (TNBC).
  • Tumor microenvironments can induce resistance and exhaustion in NK cells, hindering treatment efficacy.
  • Understanding TNBC immune evasion mechanisms is crucial for developing effective therapies.

Purpose of the Study:

  • To identify mechanisms by which TNBC cells resist NK cell-mediated killing.
  • To investigate the role of interleukin-11 (IL-11) in TNBC immune evasion.
  • To explore the potential of targeting the IL-11 pathway to enhance NK cell therapy for TNBC.

Main Methods:

  • Isolation and characterization of NK-resistant TNBC cell populations.
  • Analysis of cytokine secretion, including IL-11, by resistant TNBC cells.
  • Investigation of IL-11 trans-signaling pathway activation (sIL-11R/gp130/JAK1/STAT1/3) in NK cells.
  • Assessment of NK cell proliferation, IFNγ production, and cell cycle status.
  • Evaluation of IL-11 and sIL-11R blockade effects on NK cell activity.
  • Correlation analysis of IL-11 expression with NK cell infiltration in human TNBC tissues.

Main Results:

  • Resistant TNBC cells secrete high levels of IL-11.
  • IL-11, via trans-signaling with sIL-11R, activates gp130 on NK cells, inducing JAK1/STAT1/3 signaling.
  • This pathway leads to p21 upregulation, cell cycle arrest, and inhibition of NK cell proliferation and IFNγ production.
  • Blocking IL-11 or sIL-11R restores NK cell activity against TNBC.
  • Elevated IL-11 expression in human TNBC tissues correlates negatively with NK cell infiltration.

Conclusions:

  • IL-11 trans-signaling is a novel mechanism of immune evasion employed by TNBC cells.
  • This pathway suppresses NK cell function within the tumor microenvironment.
  • Targeting the IL-11 pathway presents a promising strategy to overcome NK cell resistance and enhance TNBC immunotherapy.
Keywords:
IL‐11NK cell exhaustionTNBCimmune evasiontrans‐signaling

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