Regulation of tumor cell death is a fundamental mechanism for tumor treatment. However, most tumors are resistant to cell death. Triggering inflammatory cell death, pyroptosis, may provide a new view of enhancing tumor cell death. Here we report a new role of Ganoderma lucidum extract (GLE) in pyroptotic cell death. Treatment with GLE (50-200 μg/mL) significantly elevated reactive oxygen species (ROS) levels and caused pyroptotic cell death in breast cancer cells. Mechanistically, GLE activates caspase 3 and further cleaves the gasdermin E (GSDME) protein to form pores on the cell membrane, releasing massive amounts of inflammatory factors in breast cancer cells. We also showed that GLE enhanced antitumor immune responses by substantially increasing the subsets of natural killer (NK) and CD8⁺T cells in the peripheral immune system and tumor microenvironment. In addition, GLE destroys multiple steps of tumor metastasis, including adhesion, migration, invasion, colonization, and angiogenesis. Collectively, these results suggest that GLE provides a potential approach for breast cancer treatment, which may complement chemotherapy or immunotherapy for cancer metastasis.