ArticleNPJ precision oncology2025
Mechanistic insights into IL-6-mediated NK cell dysfunction in NSCLC via the IRE1α-XBP1s-STAT3-UBE2S axis.
Article in NPJ precision oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- PTPN22 as a novel therapeutic target: a key intracellular checkpoint for NK cell therapy.Journal for immunotherapy of cancer · 2026Article
- LRIG2 suppresses NK cell-induced GSDME-mediated pyroptosis via the LAMP1-STAT3 pathway in glioma.Journal for immunotherapy of cancer · 2026Article
- Neutrophil extracellular traps promote liver metastasis by impairing NK cell-dependent tumor surveillance via CCDC25.Nature communications · 2026Article
- Research trends in cytokine regulation of immunotherapy in non-small cell lung cancer: a bibliometric and BERTopic analysis from 2015 to 2025.Journal of thoracic disease · 2026Article
- Modulation of the tumor microenvironment by incretins and glucagon: Metabolic and immune mechanisms (Review).Experimental and therapeutic medicine · 2026Review
- Endoplasmic reticulum stress in antitumor immunity and immunotherapy resistance: mechanisms and therapeutic implications.Molecular cancer · 2026Review
- Neutral sphingomyelinases restrict natural killer cells activity against lung cancer.Cancer immunology, immunotherapy : CII · 2026Article
- Exercise and CD8Journal of molecular medicine (Berlin, Germany) · 2026Review
- Circulating cytokines as potential dynamic biomarkers of PD-1 blockade response and prognosis in non-small cell lung cancer.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
Natural killer (NK) cell immunotherapy exhibits limited efficacy in non-small cell lung cancer (NSCLC) due to the suppressive tumor-associated immune microenvironment. Previous studies have shown that interleukin-6 (IL-6) contributes to NK cell dysfunction and decreases NKp30 expression. However, the underlying mechanisms warrant further investigation. In this study, we identified elevated IL-6 and reduced NKp30 expression correlating with NK cell dysfunction and poor prognosis in NSCLC patients. Tumoral IL-6 inversely regulated NKp30 both clinically and in vitro. Mechanistically, IRE1α-XBP1s signaling activated IL-6 transcription via XBP1s binding to the -1201/-300 promoter region. IL-6 induced STAT3-dependent UBE2S upregulation, promoting ubiquitin-mediated NKp30 degradation in NK cells. This dual regulation establishes an XBP1s/IL-6/STAT3-UBE2S axis driving NKp30 loss and functional impairment. Our findings reveal tumor-intrinsic mechanisms suppressing NK cell activity in NSCLC, proposing XBP1s, IL-6, and UBE2S as actionable targets to enhance NK-based immunotherapies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.