To investigate the mechanism of Xiaoyaosan(XYS) in alleviating breast cancer susceptibility in emotional stress mice from the perspective of macrophage phagocytosis.Methods:Twenty mice were randomly assigned into four groups：control，model，model+low-dose XYS，and model+high-dose XYS(n=5).Mice received 28 days of restraint stress for 2 h or/and XYS(3.25，6.50 g/kg) treatment daily and were subcutaneously injected with 4T1 breast cancer cells on the 7th day of stress.The tumor was photographed，and the tumor diameter and tumor weight were measured.The corticosterone(CORT) content in plasma was determined by the high performance liquid chromatography-ultraviolet(HPLC-UV) method.Immunohistochemical staining was employed to determine the phagocytosis of tumor cells by macrophages.Western blotting，RT-qPCR，and immunofluorescence staining were performed to examine the expression of low-density lipoprotein receptor-related protein 1(LRP1)，signal-regulatory protein α(SIRPα)，and miRNAs in the tumor tissue.Results:Compared with the model group，XYS relieved emotional stress-evoked breast cancer susceptibility，the mechanism of which was associated with inhibiting the phagocytosis of tumor cells by macrophages through evoking LRP1 expression and down-regulating SIRPα expression(P<0.05).Further，XYS regulated the phagocytosis by up-regulating the expression of miRNA-4259/6680-5p/7847-3p(P<0.05).Conclusion:XYS ameliorates emotional stress-induced breast cancer susceptibility by preventing the disturbance of LRP1-SIRPα signals and promoting the phagocytosis of tumor cells by macrophages.