Fig. 3: The immunosuppressive tumor microenvironment of neuroblastoma. | Oncogene

Fig. 3: The immunosuppressive tumor microenvironment of neuroblastoma.

From: Dissecting neuroblastoma heterogeneity through single-cell multi-omics: insights into development, immunity, and therapeutic resistance

Fig. 3

Single-cell and spatial multi-omics analyses have revealed a complex immunosuppressive network in the NB TME. Tumor-associated macrophages (TAMs) and neutrophils act as central mediators of immune evasion and stromal remodeling. MIF⁺ TAMs interact with tumor and stromal cells through MIF–CD74/CD44/CXCR4 signaling, while SPP1⁺ TAMs promote angiogenesis and extracellular matrix (ECM) reorganization via SPP1–ITGB1–STAT3 and VEGF pathways. Neutrophils secrete CXCL8 and S100A8/A9, activating the CXCR2–MAPK/NF-κB axis to induce immune exhaustion and PD-L1 upregulation. Cancer-associated fibroblasts (CAFs) further reinforce immune exclusion by releasing TGF-β, CXCL12, COL1A1, and FN1, forming a collagen-rich physical barrier that limits effector T-cell infiltration. Endothelial–immune crosstalk, exemplified by LGALS9–HAVCR2 (TIM-3) interactions, contributes to vascular immune suppression. In parallel, monocytes and MDSCs support macrophage recruitment and differentiation through MIF–CD74/CD44 and SPP1–ITGAV signaling. Collectively, these coordinated cellular and molecular interactions establish a highly suppressive microenvironment that promotes immune escape, angiogenesis, and tumor progression in high-risk and relapsed NB.

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