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Mechanistic insights into IL-6-mediated NK cell dysfunction in NSCLC via the IRE1α-XBP1s-STAT3-UBE2S axis

Yazhen Wang1, Zichan Guo2, Anqi Xu1,3

  • 1Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.

NPJ Precision Oncology
|November 18, 2025
PubMed

Insights

Natural killer (NK) cell immunotherapy is less effective in non-small cell lung cancer (NSCLC) because tumors suppress NK cells. This study reveals a mechanism involving XBP1s, IL-6, and UBE2S that reduces NKp30, impairing NK cell function in NSCLC.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Natural killer (NK) cell immunotherapy shows limited success in non-small cell lung cancer (NSCLC) due to the tumor immune microenvironment.
  • Interleukin-6 (IL-6) is implicated in NK cell dysfunction and reduced NKp30 expression, but the precise mechanisms are unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying NK cell dysfunction in NSCLC.
  • To identify key regulators of NKp30 expression and function in the context of NSCLC.

Main Methods:

  • Correlation analysis of IL-6 and NKp30 expression with NK cell function and prognosis in NSCLC patients.
  • In vitro studies to elucidate the regulatory pathways of IL-6 and NKp30.
  • Analysis of the IRE1α-XBP1s signaling pathway and its role in IL-6 transcription.
  • Investigation of IL-6-induced STAT3-dependent UBE2S upregulation and its effect on NKp30 degradation.

Main Results:

  • Elevated IL-6 and reduced NKp30 expression were observed in NSCLC patients, correlating with poor prognosis and NK cell dysfunction.
  • Tumoral IL-6 was found to inversely regulate NKp30 expression both clinically and in vitro.
  • The IRE1α-XBP1s pathway was identified as a key activator of IL-6 transcription.
  • IL-6 was shown to induce STAT3-dependent UBE2S upregulation, leading to NKp30 degradation in NK cells.
  • A novel XBP1s/IL-6/STAT3-UBE2S axis was established, driving NKp30 loss and NK cell functional impairment.

Conclusions:

  • Tumor-intrinsic mechanisms involving the XBP1s/IL-6/STAT3-UBE2S axis contribute to NK cell suppression in NSCLC.
  • Targeting XBP1s, IL-6, or UBE2S may represent a viable strategy to enhance NK cell-based immunotherapies for NSCLC.

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