Metabolic Alterations in Macrophage Subtypes Propel Immune and Stromal Remodeling in Neurofibroma's Malignant Progression

Abstract

Neurofibromatosis type 1 (NF1) is characterized by the development of benign plexiform neurofibromas (PNFs). In 10%–15% of patients, these tumors undergo malignant transformation into aggressive malignant peripheral nerve sheath tumors (MPNSTs). The underlying mechanisms driving this malignant progression remain poorly understood, hindering the development of effective therapies. To address this gap, we performed single-cell RNA sequencing on nine PNF and five MPNST samples. Our analysis revealed tumor microenvironment remodeling during malignant progression, marked by a significant increase in immune cells. Within the macrophage compartment, we identified three distinct SPP1⁺ subpopulations. Among these, the SPP1⁺KYNU⁺ subset exhibited pronounced upregulation of genes related to tryptophan metabolism. This metabolically active macrophage population exhibited strong interaction with POSTN⁺ fibroblasts enriched in MPNSTs. Functional experiments found that this crosstalk promotes fibroblast activation and enhances migratory capacity. Furthermore, the metabolic reprogramming of SPP1⁺KYNU⁺ macrophages was associated with the establishment of an immunosuppressive microenvironment characterized by T cell dysfunction. Collectively, our findings define a central role for SPP1⁺KYNU⁺ macrophages in coordinating both stromal remodeling and immune suppression during MPNST progression. These results not only advance our understanding of NF1-associated tumorigenesis but also identify tryptophan metabolism as a promising therapeutic target and potential diagnostic biomarker for MPNSTs.

Keywords

extracellular matrix fibroblasts / malignant progression / neurofibromatosis type 1 / single-cell RNA sequencing / tumor-associated macrophages

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