For a study, researchers looked at the spatial and transcriptomic characteristics of perineural invasion (PNI)-positive and PNI-negative nerves to fill in these knowledge gaps. The applicability of PNI as a stand-alone prognostic predictor had not been demonstrated, and its diagnostic criteria differed. Slices of tissue from 142 people were stained with S100 and cytokeratin antibodies. The mass and perimeter of the tumor were found to contain nerves. They measured the nerve’s diameter and the distance between it and the tumor in addition to performing survival studies. Using the NanoString GeoMx Digital Spatial Profiler Transcriptome Atlas, a spatial transcriptomic analysis of nerves located at various tumor distances was performed. PNI accurately indicates a worse prognosis in patients with lymph nodes devoid of metastases. Even when a PNI-negative tumor was detected using current criteria, patients with a close nerve-tumor distance had a dismal prognosis. The poor prognosis of individuals with significant nerve(s) in the tumor mass suggested that even PNI-negative nerves can promote tumor growth. A spatial transcriptomic study of more than 18,000 genes validated the diagnostic criteria; nerves close to cancer showed alterations in stress and growth response, which became less pronounced with growing nerve-tumor distance. Using human tissue and in vitro tests, these findings were confirmed. This work was the first to examine the relationship between clinical outcomes and transcriptome profile using high-throughput gene expression profiling in nerves. Their findings shed light on the relationships between nerves and cancer by demonstrating how cancer-induced injury reduces neurogenesis. They also supported moving away from the current subjective standards for PNI classification and toward a system based on the distance between the nerve and the tumor.