Docetaxel induced activation of GSDME pathway and pyroptosis enhance immune lethality in prostate cancer cells

BACKGROUND: Immunotherapy has emerged as a promising approach in prostate cancer treatment, albeit with less efficacy compared to lung and esophageal cancers. Recent studies have explored the combination of chemotherapy, specifically docetaxel, with immunotherapy to enhance treatment outcomes. Docetaxel has been reported to be associated with the pyroptosis pathway, which can alter the tumor microenvironment. Therefore, we attempted to explore the specific molecular mechanism by which docetaxel enhances immunotherapy, with the aim of providing new insights for the immunotherapy of prostate cancer patients. METHODS: Immunohistochemical analysis was employed to assess changes in immune markers in prostate cancer tissues pre- and post-docetaxel treatment. Functional assays, including LDH release and flow cytometry, validated cell responses. Molecular interactions were investigated using co-immunoprecipitation and GST pull-down assays to elucidate the binding mechanism between GSDME and SKP2. The detailed mechanism of GSDME activating cellular immunity was analyzed by single cell sequencing. A xenograft model was utilized to confirm the therapeutic efficacy and molecular role of docetaxel combined with immunotherapy. RESULTS: Docetaxel chemotherapy increased immune-related lymphocytes in patient samples, suggesting an enhanced immune response. Furthermore, docetaxel induced pyroptosis in prostate cancer cells via the GSDME pathway, influencing the immune microenvironment without affecting cell viability. GSDME was found to undergo SKP2-mediated ubiquitination and degradation via the proteasome pathway, this process can be blocked by the inhibition of GSDME phosphorylation through the AKT pathway mediated by docetaxel. The results of single-cell sequencing suggest that GSDME can recruit CD8 + T lymphocytes and NK cells in prostate cancer. The experimental data indicate that the combination of docetaxel and avelumab can achieve better therapeutic effects. CONCLUSION: Our findings suggest that docetaxel enhances immunotherapy efficacy in prostate cancer by modulating pyroptosis pathways. This approach may offer a novel therapeutic strategy for clinical management.