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The Astragalus membranaceus polysaccharide (APS4) with direct cytotoxicity on various cancer cells has been prepared in our previous study, while the underlying therapeutic role of APS4 on solid tumors in vivo hasn't been investigated yet. Therefore, in this paper, the lymphocytes-mediated antitumor and immunoregulatory activities of APS4 were researched by establishing S180 tumor-bearing mice model. Flow cytometry analysis revealed that APS4 could effectively regulate the percentages of CD3+, CD4+, CD8+ T cells and CD19+ B cells in thymus, peripheral blood and spleen of S180 tumor-bearing mice, dose-dependently. H&E staining and cell cycle determination of solid tumors manifested that APS4 treatment could significantly inhibit the growth of solid tumors by inducing cells apoptosis. Furthermore, two-dimensional electrophoresis and western blot analysis further demonstrated that APS4 could activate antitumor-related immune cells and promote anaerobic metabolism of tumor microenvironment, thereby causing the apoptosis of S180 tumor cells. These data implicated that APS4 could be used as a potential dietary supplement for immune enhancement. [ABSTRACT FROM AUTHOR]