Molecular mechanisms and clinical significance of perineural invasion in malignancies: the pivotal role of tumor-associated Schwann cells in cancer progression and metastasis

Perineural invasion (PNI) is a pathological process wherein cancer cells invade and spread along peripheral nerves, contributing to tumor aggressiveness and poor clinical outcomes, including increased recurrence, metastasis, and reduced survival. Tumor-associated Schwann cells (SCs) play a pivotal role in facilitating PNI by promoting epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, and immune modulation. These cells actively support tumor progression through neurotrophin, cytokine, chemokine, and neurotransmitter signaling, enhancing cancer cell migration along neural pathways. Recent advances in imaging techniques, single-cell transcriptomics, and molecular profiling have provided deeper insights into the tumor microenvironment’s role in PNI. Emerging therapeutic strategies targeting neurotrophin-mediated signaling and SC-tumor interactions have shown promise in preclinical models. However, significant research gaps remain, particularly in understanding the heterogeneity of SCs and their molecular subtypes in PNI across different malignancies. This review highlights the clinical significance, molecular mechanisms, and potential therapeutic targets associated with PNI. A comprehensive understanding of tumor-SC interactions is essential for developing targeted interventions to mitigate PNI-driven malignancies. Future research should focus on integrating multi-omics approaches and novel therapeutics to improve early detection and treatment, ultimately enhancing patient outcomes. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.