Integrative Multi-Omics Analysis Identifies an SPP1-Associated Spatial Mesenchymal–Myeloid Program in Glioblastoma

Background: Glioblastoma (GBM) is characterized by pronounced transcriptional plasticity and a highly structured immune microenvironment, yet the molecular features associated with tumor-state transitions and immune remodeling remain incompletely understood. Methods: We used an integrative multi-omics framework to examine how secreted phosphoprotein 1 (SPP1) relates to tumor microenvironment organization in human gliomas. Results: Single-cell analyses associated SPP1 with myeloid populations, mesenchymal-like (MES-like) malignant states, inflammatory regulatory programs, and inferred ligand–receptor co-expression patterns involving SPP1–CD44 and SPP1–integrin pairs. Spatial transcriptomic analyses showed that SPP1-high regions were enriched for estimated myeloid abundance, MES-like tumor signal, and ECM/angiogenic programs, supporting an SPP1-associated spatial mesenchymal–myeloid program in GBM. Computational perturbation analyses provided network-level support for SPP1–CD44-associated stress-responsive programs. HPA immunohistochemistry provided tissue-level protein context for SPP1 and related mesenchymal/receptor-associated components. Ivy GAP analysis showed enrichment of SPP1-associated features in core-like anatomic compartments, and CODEX spatial protein imaging provided antibody-panel-based contextual support for mesenchymal–myeloid-associated features. In the TCGA-GBM cohort, elevated SPP1 expression and an SPP1-associated mesenchymal signature were associated with poorer overall survival. Conclusions: These findings support an inferential model in which SPP1 is associated with spatial mesenchymal–myeloid organization in GBM and nominate SPP1-associated programs as candidate readouts of tumor plasticity, inflammatory myeloid remodeling, and spatial tumor microenvironment organization.