CSF1R通过PI3K/AKT信号通路影响食管癌免疫治疗疗效OA

Objective To investigate whether colony-stimulating factor 1 receptor(CSF1R)enhances the effi-cacy of immunotherapy in esophageal cancer through the phosphatidylinositol 3-kinase/protein kinase B(PI3 K/AKT)signaling pathway,and to provide experimental evidence for precision immunotherapy in gastroesophageal malignancies.Methods A mouse subcutaneous xenograft model of esophageal cancer was established.Tumor growth was monitored by measuring tumor volume and weight.Western blot analysis was performed to determine the effects of CSF1R overexpression on the expression of PI3K/AKT signaling pathway-related proteins,including PI3K,AKT,mTOR,phosphorylated PI3K(p-PI3K),phosphorylated AKT(p-AKT),and phosphorylated mTOR(p-mTOR).Tumor-bearing mice were di-vided into the following groups:negative control,CSF1R overexpression,LY294002 treatment(PI3K inhibitor),M2 macrophage inhibitor treatment,CSF1R inhibitor treatment,and combined treatment with an M2 macrophage inhibitor and a CSF1R inhibitor.After treatment,general condition and tumor volume were recorded,and tumor tissues were collected.Flow cytometry was used to detect the expression of immune markers CD45,F4/80,and CD206.Enzyme-linked immu-nosorbent assay(ELISA)was performed to measure the expression of the CSF1R ligand CSF1.The effects of LY294002,CSF1R inhibitors,and M2 macrophage inhibitors on immunotherapy efficacy in CSF1R-overexpressing esophageal cancer were evaluated.Results CSF1R overexpression significantly promoted the activation of key proteins in the PI3K/AKT signaling pathway.In vivo imaging demonstrated that treatment with the CSF1R inhibitor PLX3397 and the PI3Kγ inhibitor Eganelisib significantly suppressed tumor growth(P＜0.05).Flow cytometry and ELISA analyses revealed that PLX3397 and Eganelisib altered the immune microenvironment of esophageal tumors.Both single-agent and combined treatments significantly modulated macrophage polarization and reduced the number of immunosuppressive macrophages within the tumor microenvironment,thereby improving the immune milieu and effectively inhibiting tumor growth(P＜0.05).Conclusion CSF1R promotes M2 macrophage polarization within the tumor immune microenvironment by activating the PI3K/AKT signaling pathway,thereby facilitating malignant progression of esophageal cancer.Targeting CSF1R overex-pression or modulating macrophage polarization within the tumor microenvironment may represent a promising strategy for precision immunotherapy in esophageal cancer.