Background <p>Gastric cancer (GC) is a malignant tumor prevalent worldwide. ESPN belongs to actin-binding protein family and serves as an oncogene in various cancers. Immune escape is one of the core mechanisms underlying the occurrence and resistance of GC.</p> Aims <p>This research aimed to explore ESPN function and mechanism GC.</p> Methods <p>ESPN expression in GC was fanalyzed through The Cancer Genome Atlas Program (TCGA). GC patient overall survival (OS), progression-free survival (PFS) and post-progression survival (PPS) rate were assessed using Kaplan-Meier Plotter database. ESPN levels were tested using qRT-PCR and Western blot. After knockdown of ESPN in GC cells, ESPN function and mechanism in GC was verified by Cell Counting Kit-8, EdU, Transwell, Western blot, ELISA and immunofluorescence. Furthermore, ESPN roles in vivo were assessed by tumor xenograft model, immunohistochemistry, and Western blot.</p> Results <p>ESPN was overexpressed in GC, and patients with huge ESPN expression had poorer prognosis in terms of OS, PFS and PPS. ESPN expression was related to TNM stage and distant metastasis. Also, knocking down ESPN reduced GC cell growth and immune escape. Importantly, interference with ESPN inactivated AKT/NF-κB axis in GC cells, and silencing ESPN repressed GC cell proliferation, invasion and immune escape, while these impacts were abolished after SC79 (AKT pathway activator) addition. Meanwhile, ESPN knockdown reduced GC proliferation and immune escape in vivo through decreased tumor weight, IL-10 expressions, p-AKT and p-NF-κB protein levels, yet increased IFN-γ expression.</p> Conclusion <p>Silencing ESPN reduced GC cell proliferation, invasion and immune escape through inactivating AKT/NF-κB.</p> Graphical abstract <p></p>