Neuron‐Derived MIF Engages VCAM1 to Fuel a Self‐Amplifying CXCL8 Loop That Drives Perineural Invasion and Metastasis in Gastric Cancer

ABSTRACT Background : Perineural invasion (PNI) is common in gastric cancer and predicts poor prognosis, but the molecular mechanisms underlying tumour–nerve crosstalk remain unclear. Methods : Transcriptomic data from TCGA and GEO were integrated to identify PNI regulators, with validation in surgical specimens. Mechanistic studies used tumor–neuron Transwell co‐culture, siRNA/lentiviral perturbation, Western blot, immunofluorescence, ELISA, co‐immunoprecipitation, and GST pull‐down. Functional effects were assessed via CCK‐8/Transwell assays, a sciatic nerve invasion xenograft model, and an orthotopic gastric cancer model with neuron‐specific MIF conditional knockout mice. Results : High CXCL8/VCAM1 expression correlates with poor overall survival, distant metastasis, and is upregulated in PNI‐positive tumours. Mechanistically, CXCL8 promotes neuronal MIF expression, while MIF directly binds VCAM1 and enhances tumour CXCL8 expression. VCAM1‐mediated CXCL8 upregulation drives tumour proliferation and invasion. In vivo, blocking CXCL8/VCAM1 or neuron‐specific MIF deletion reduces tumour growth and neural invasion. Conclusions : A MIF–VCAM1–CXCL8 positive‐feedback axis linking neural activity to gastric cancer progression and PNI is identified, providing prognostic biomarkers and actionable therapeutic targets.