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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.