LRP12 promotes gastric cancer progression through AKT/mTOR signaling and M2 macrophage-mediated immunosuppression

Tumor-associated inflammation and macrophage polarization drive gastric cancer (GC) progression. We aimed to identify inflammation-related biomarkers that predict prognosis and modulate the tumor immune microenvironment, focusing on LDL receptor-related protein 12 (LRP12). We integrated public datasets with an in-house cohort to build an immune-related prognostic model based on inflammatory response-related genes (IRRGs) and to nominate candidate genes. Single-cell transcriptomics were used to map cell-type enrichment. Key findings were validated by multiplex immunofluorescence/immunohistochemistry, LRP12 overexpression and knockdown in GC cell lines, in vitro proliferation and invasion assays, western blotting for signaling pathways, and xenograft models. LRP12 was identified as a differentially expressed IRRG-associated gene and emerged as a robust prognostic marker, enriched in malignant cells and macrophage populations. High LRP12 expression correlated with poorer overall survival and with M2 macrophage markers (CD163, CD206). Functional studies using both overexpression and knockdown showed that LRP12 promotes GC cell proliferation and invasion, while xenografts of LRP12-knockdown cells exhibited reduced tumor growth. Mechanistically, LRP12 overexpression activated the AKT/mTOR pathway, reflected by increased phosphorylation of AKT and mTOR. LRP12-associated signatures were linked to an immunosuppressive microenvironment characterized by M2 macrophage infiltration and may indicate responsiveness to therapies that repolarize M2-like tumor-associated macrophages. LRP12 is a prognostic biomarker in GC that promotes tumor progression via AKT/mTOR signaling and M2 macrophage-mediated immunosuppression, with potential to inform personalized therapeutic strategies.