Schwann cell reprogramming and immune regulation in the cancer microenvironment

Schwann cells are peripheral glia with established roles in nerve support and repair. In cancer, tumor-derived factors, inflammatory mediators and metabolic stress can redirect this repair program and generate tumor-associated Schwann cell (TASc) states. These cells are enriched around nerves and invasive fronts, where they have been linked to perineural invasion, extracellular matrix remodeling and changes in immune-cell localization and function. This Review summarizes recent work on the origin, recruitment and reprogramming of TAScs, with emphasis on molecular and cellular mechanisms rather than descriptive pathology alone. We discuss how transcriptional regulators, chemokines, neurotrophic factors, extracellular vesicles and metabolic pathways shape Schwann cell states in tumors, and how these states communicate with cancer cells, macrophages, T cells and natural killer cells. We also consider single-cell and spatial transcriptomic studies that have refined TASc classification, while noting the limitations of marker-based annotation, model systems and cross-tumor extrapolation. Finally, we evaluate the potential use of TASc-associated programs as biomarkers and therapeutic entry points, particularly in tumors with perineural invasion or resistance to immunotherapy. A critical assessment of current evidence indicates that Schwann cell reprogramming is a context-dependent process that should be studied as part of the wider cellular organization of the cancer microenvironment.