Cancer-Associated Fibroblasts in Perineural Invasion: Biological Roles and Therapeutic Strategies

Perineural invasion (PNI), the process of tumor cell infiltration of nerves, is a pathological feature of aggressive tumor behavior, correlating with therapeutic resistance and poor clinical outcomes. Cancer-associated fibroblasts (CAFs) have recently emerged as key regulators of PNI. CAFs drive PNI progression through multifaceted mechanisms, including dynamic remodeling of CAF subtypes, neural microenvironment remodeling, and enhancement of tumor–nerve crosstalk via neurotrophic signaling. While various therapeutic approaches targeting CAF surface markers, secreted factors, and intracellular signaling pathways are under investigation, none have yet been translated into clinical practice for PNI management. This review synthesizes current understanding of CAF-mediated PNI, highlights critical knowledge gaps, and proposes future directions. Here, we conceptualize CAF-mediated PNI as a coordinated process linking CAF subtype dynamics, neural niche remodeling, and tumor–nerve crosstalk, rather than as a collection of isolated pro-invasive mechanisms.