Stromal Regulation of Tumor Perineural Invasion: A Multicellular and Neuro-Ecological Perspective

Perineural invasion (PNI) is an aggressive driver of tumor progression, therapeutic resistance, and poor prognosis across diverse malignancies. Traditionally viewed as a tumor cell-autonomous process, PNI is increasingly recognized as a dynamic phenomenon shaped by the tumor-nerve-stromal ecosystem. This review synthesizes recent advances to reframe neural invasion as a coordinated, multicellular process governed by reciprocal interactions within this niche. We delineate how stromal and immune components, including cancer-associated fibroblasts, Schwann cells, immune cells, and the extracellular matrix, facilitate PNI through structural remodeling and biochemical signaling within the tumor-nerve interface. These coordinated interactions drive nerve reorganization and local immune reprogramming, collectively establishing a permissive niche that supports tumor spread along neural routes. By integrating these interconnected mechanisms into a neuro-ecological framework, we clarify how networked tumor-stromal-neural remodeling underlies neural dissemination. This perspective identifies therapeutic vulnerabilities within the neural microenvironment and suggests that disrupting bidirectional crosstalk between tumor cells and their stromal partners may offer strategies to limit neural spread and improve clinical outcomes.