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Perineural invasion (PNI) is a biological characteristic commonly observed in pancreatic cancer. Although PNI plays a key role in pancreatic cancer metastasis, recurrence, and poor postoperative survival, its mechanism is largely unclarified. Clinical sample analysis and endoscopic ultrasonographic elasticity scoring indicated that cancer-associated fibroblasts (CAFs) were closely related to the occurrence of PNI. Furthermore, CAF-derived extracellular vesicles (EVs) were involved in PNI in dorsal root ganglion coculture and mouse sciatic nerve models. Next, we demonstrated that CAFs promoted PNI through extracellular vesicle transmission of PNI-associated transcript (PIAT). Mechanistically, PIAT specifically bound to YBX1 and blocked the YBX1-Nedd4l interaction to inhibit YBX1 ubiquitination and degradation. Furthermore, PIAT enhanced the binding of YBX1 and PNI-associated mRNAs in a 5-methylcytosine (m5C)–dependent manner. Mutation of m5C recognition motifs in YBX1 or m5C sites in downstream target genes reversed PIAT-mediated PNI. Consistent with these findings, analyses using a KPC mouse model demonstrated that the PIAT/YBX1 axis enhanced PNI through m5C modification. Clinical data suggested that the PIAT expression in the serum EVs of patients with pancreatic cancer was associated with the degree of neural invasion and prognosis. Our study revealed the important role of the PIAT/YBX1 signaling axis in the tumor microenvironment (TME) in promoting tumor cell PNI and provided a new target for precise interference with CAFs and RNA methylation in the TME to suppress PNI in pancreatic cancer. Editor's summary: Pancreatic cancer has a very poor prognosis and is often characterized by perineural invasion (PNI); however, the role that PNI plays in postoperative survival has been unexplored. Here, Zheng et al. evaluate the role PNI plays in pancreatic cancer prognosis and show that cancer-associated fibroblasts (CAFs) induce PNI in tumors through CAF-derived extracellular vesicles (EVs). They show that these EVs are packaged with PNI-associated transcript (PIAT) that enhances PNI in mouse models and induces worse survival. PIAT represents a potential target for reducing PNI in pancreatic cancer and perhaps improving survival for patients that requires further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]