Spatiotemporal profiling of endocytic regulators in the immunosuppressive TAM microenvironment of glioma

Abstract

Endocytosis plays a pivotal role in shaping the immunosuppressive landscape of gliomas, yet its spatial dynamics within the tumor microenvironment remain incompletely understood. Here, we integrated single-cell and spatial transcriptomic analyses to characterize endocytosis-related regulators involved in immune remodeling. Among them, FCGR2B, CLEC7A, and LYAR emerged as key modulators associated with the spatiotemporal heterogeneity of tumor-associated macrophages (TAMs) and malignant cells. These genes displayed regionally elevated transcript levels from the tumor–normal interface toward perivascular and necrotic regions, accompanied by progressively stronger spatial co-localization with M2-like macrophages across multiple spatial scales. Cell–cell communication analysis revealed that these regulators were linked to activation of endocytosis-associated signaling pathways, including SPP1, GRN, and PSAP. A prognostic risk score derived from their expression effectively stratified patients by molecular subtype and clinical outcome, and SHAP-based model interpretation quantified the contribution of each gene to risk prediction. Immunohistochemistry and Western blot analyses further validated their elevated protein expression in high-grade glioma tissues. Collectively, this spatial multi-omic framework delineates endocytosis-associated immune remodeling in glioma and identifies FCGR2B, CLEC7A, and LYAR as potential biomarkers and therapeutic targets for disrupting immunosuppressive niches.