Mechanistic Insights into IL-6-Mediated NK Cell Dysfunction in NSCLC via the IRE1α-XBP1s-STAT3-UBE2S Axis

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.