LRIG2 suppresses NK cell-induced GSDME-mediated pyroptosis via the LAMP1-STAT3 pathway in glioma.

Authors

Xiaoshuang Hou, Lan Lin, Po Zhang, Youwei Li, Minhai Dong, Sui Chen, Xiaohu Oyang, Jingbo Wang, Fangling Cheng, Xiaopeng Li, Min Zhao, Feng Mao, Xingjiang Yu, Desheng Hu, Baofeng Wang, Dongsheng Guo

Published in

Journal for immunotherapy of cancer. Volume 14. Issue 9. Sep 15, 2026. Epub Sep 15, 2026.

Abstract

Gliomas are resistant to current therapies, and natural killer (NK) cell-based immunotherapy shows limited efficacy. Gasdermin E (GSDME)-mediated pyroptosis contributes to NK-induced tumor killing, but NK cell dysfunction in the glioma microenvironment remains poorly understood. This study investigates whether leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2) enable glioma cells to evade NK-induced pyroptosis and elucidates the underlying mechanism.
We used in vitro co-culture systems with glioma cell lines (LN229, HS683, FU) and primary NK cells or NK92-MI cells to assess cytotoxicity, pyroptosis (lactate dehydrogenase release, morphology, GSDME cleavage by western blot), and cytokine release (Cytometric Bead Array). In vivo, orthotopic glioma models in C57BL/6 and RAG1-KO mice received intracranial stimulator of interferon genes agonist diABZI. Mechanistic dissection involved biochemical approaches (co-immunoprecipitation-mass spectrometry and membrane protein extraction), cellular imaging (immunofluorescence), and genetic perturbation via CRISPR-mediated knockdown.
NK cells induced GSDME-dependent pyroptosis in glioma cells in vitro, but this was impaired in vivo due to suppressed NK cytotoxicity. LRIG2 was highly expressed in gliomas; its overexpression inhibited GSDME cleavage, pyroptosis, and glioma cell death, whereas LRIG2 knockdown enhanced these effects. Mechanistically, soluble LRIG2 shed from glioma cells bound to lysosomal-associated membrane protein 1 (LAMP1) on NK cells, upregulating phosphorylated-signal transducer and activator of transcription (p-STAT3) via Janus kinase 1 (JAK1) and reducing granzyme B and perforin release. Disrupting the LRIG2-LAMP1-STAT3 axis by LRIG2 knockdown or STAT3 knockout restored NK cytotoxicity and GSDME cleavage. Combining LRIG2 knockdown with diABZI significantly enhanced NK granzyme B expression and prolonged mouse survival.
LRIG2 enables glioma immune evasion by suppressing NK-induced GSDME-mediated pyroptosis via the LAMP1-STAT3 pathway. Targeting this axis represents a promising strategy to enhance NK cell-based immunotherapy for gliomas, positioning LRIG2 as a potential biomarker and therapeutic target.

PMID:
42744390
Bibliographic data and abstract were imported from PubMed on 16 Sep 2026.

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