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Abstract Background Selenium supplementation can be used to treat tumors. However, inorganic selenium is highly toxic, and natural organic selenium is extremely rare. Polysaccharides can improve drug bioavailability and targeting. Lentinan is a polysaccharide that has been approved as an anti-cancer drug in Japan and China. Methods Lentinan, an antitumor polysaccharide extracted from Lentinus edodes , was conjugated with seleninic acid to be transformed into ester (Se–lentinan) and utilized as drug carrier. The enhancement of the anti-tumor effects of Se–lentinan was evaluated by cell viability, cell cycle, migration, and transwell assays and animal xenograft models. The effects of Se-lentinan on the expression levels of epithelial–mesenchymal transition (EMT) markers were determined through immunofluorescence, Western blot, and immunohistochemistry analyses. Results Se–lentinan inhibited the invasiveness of B16-BL6 and HCT-8 cells by suppressing EMT. In vivo, Se–lentinan significantly inhibited tumor growth and metastasis of the transplanted melanoma and colon cancer cells and showed less toxicity than sodium selenite. Moreover, Se–lentinan reduced the accumulation of selenium in the liver and kidney tissues of mice and exhibited low organ toxicity. Conclusion The antitumor activity of selenium was enhanced greatly, and its side effects were reduced with the use of lentinan as drug carrier. Highlights • Lentinan was utilized as a drug carrier. • Se-lentinan inhibited the invasion abilities and growths of Melanoma. • Se-lentinan inhibited tumor growth and metastasis with less toxicity. • Se-lentinan reduced the accumulation of selenium in the tissues of mice. [ABSTRACT FROM AUTHOR]