Unraveling the role of perineural invasion in cancer progression across multiple tumor types.

Perineural invasion (PNI) refers to the infiltration of tumor cells into the connective tissue of nerves and is increasingly recognized as a pathological hallmark of multiple cancers, including pancreatic, prostate, colorectal, breast, and head and neck malignancies. PNI is associated with aggressive tumor behavior, an increased risk of recurrence, and poor patient survival. This review consolidates current mechanistic insights into PNI, highlighting immune-neural crosstalk, Schwann cell activation, tumor-nerve feedback loops, and conserved neurotrophic signaling axes. In addition to these shared features, we identify tumor-specific drivers, such as neural progenitor cell involvement in breast cancer, glutamate/NMDA receptor signaling in pancreatic cancer, and epigenetic regulators in gastric and head and neck cancers. A key clinical advancement involves integrating artificial intelligence-driven imaging and machine learning tools for enhanced detection, classification, and prognostic assessment of PNI. These technologies provide scalable, reproducible alternatives to traditional histopathology and underscore the need for standardized diagnostic protocols. By synthesizing molecular, cellular, and computational findings, this review outlines a strategic framework for identifying actionable targets within the nerve-tumor interface. Ultimately, understanding the complex biology of PNI is critical for developing targeted therapies and precision oncology strategies that may reduce recurrence and improve outcomes for patients with high-risk, nerve-invasive tumors.