SERPINE1 Facilitates Metastasis in Gastric Cancer Through Anoikis Resistance and Tumor Microenvironment Remodeling

Abstract

SERPINE1 is a serine protease inhibitor upregulated in various malignancies and pivotal in gastric cancer (GC) metastasis and the tumor microenvironment (TME). This study elucidates the mechanisms by which SERPINE1 mediates anoikis resistance and fosters an immunosuppressive TME in advanced GC. SERPINE1 is highly expressed in GC tissues and metastatic lesions and serves as an independent risk factor for poor prognosis. The transcriptional activation of SERPINE1 by CEBPB triggers the PI3K/AKT and EMT signaling pathway via autocrine mechanisms, enhancing anoikis resistance and metastatic potential in GC cells. Furthermore, SERPINE1 facilitates M2 macrophage polarization by binding to lipoprotein receptor-related protein 1 (LRP1) in a paracrine manner, suppressing CD8+ T-cell infiltration and functionality in the TME. Therapeutic intervention combining SERPINE1 inhibition with PD-1 blockade exhibits synergistic antitumor effects. Clinically, high SERPINE1 expression is associated with an increased risk of recurrence following immune checkpoint inhibitor therapy in patients with advanced GC. These findings suggest that SERPINE1 is a critical driver of GC progression through anoikis resistance and TME remodeling. Hence, SERPINE1 can offer a promising therapeutic target and represent a predictive biomarker for immunotherapy outcomes in GC.