PTPRZ1–MET fusion and induction of reprogrammed immuno-microenvironment via MET–IFN-β–LGALS9 signaling pathway during IDH-mutant glioma progression.

Abstract

e14088 Background: Recurrent IDH-mutant high-grade gliomas are difficult to treat, with limited effective targeted or immune therapies. PTPRZ1–MET (ZM) fusion is a recurrent alteration enriched during malignant progression, present in ~15% of secondary glioblastomas and associated with significantly worse survival (median OS 127 vs 248 days in ZM-negative sGBM). However, how ZM fusion reshapes the immune microenvironment in recurrent IDH-mutant gliomas and whether it creates targetable immune vulnerabilities remain unclear. Here, we investigated ZM fusion–associated immune remodeling and evaluated the rationale for combined MET and LGALS9 targeting. Methods: Single-cell RNA sequencing was performed on six recurrent IDH-mutant high-grade gliomas. Myeloid populations were subclustered and annotated using module-based approaches. Ligand–receptor analyses compared intercellular communication by fusion status. A fusion-associated macrophage signature was used to build prognostic models via Cox regression, LASSO, and random forest selection, followed by Kaplan–Meier analysis. MET and LGALS9 expression were validated by immunohistochemistry and multiplex immunofluorescence with spatial line-scan analysis. ZM fusion was introduced into glioma cell models and confirmed by Western blot and imaging. Therapeutic efficacy was evaluated in an immunocompetent orthotopic IDH-mutant/ZM fusion GL261 model treated with anti-LGALS9 antibody (RG9-1), the MET inhibitor vebreltinib, or their combination. Results: scRNA-seq revealed marked myeloid heterogeneity and identified a ZM fusion–associated microglia-like macrophage program characterized by enhanced antigen presentation and myeloid activation, which supported a prognostic risk score stratifying patient outcomes. Cell–cell communication analysis showed signaling rewiring in fusion-positive tumors, highlighting strengthened MET–LGALS9 interactions between tumor and myeloid compartments. Transcriptomic profiling demonstrated elevated type I interferon responses in fusion-positive tumor cells, with altered IFN-I regulatory nodes in both tumor and microglial populations. Tissue validation confirmed cell-type specificity, with higher MET expression in tumor cells and higher LGALS9 in myeloid/microglial cells (P<0.001), as well as close spatial proximity. In vivo, combined RG9-1 and vebreltinib treatment achieved the strongest tumor suppression and longest survival compared with monotherapy or control. Conclusions: PTPRZ1–MET fusion defines a recurrent subset of IDH-mutant gliomas with immunosuppressive remodeling. Integrated evidence supports a fusion-associated MET–IFN-β–LGALS9 axis linking tumor-intrinsic interferon signaling to macrophage-mediated immune regulation, providing a rationale for combined MET and LGALS9 targeting.