Related Experiment Video
Updated: Aug 16, 2026
Examination of Pyroptosis by Flow Cytometry
Published on: May 31, 2024
GSDME mediated pyroptosis drives CCL5 secretion and dictates proteasome inhibitor efficacy in solid tumors
Dongyang Tang1, Josh Haipeng Lei1, Shiqi Lin1
1Cancer Center, Faculty of Medicine, University of Macau, Macao Special Administrative Region of China; MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao Special Administrative Region of China.
Abstract:
Proteasome inhibitors show limited efficacy against solid tumors. We previously show the combination of Bortezomib with ammonium tetrathiomolybdate (TM) or AMD3100 could inhibit breast cancer growth rely on intact immune system. However, it remains to be explored the broad application of these drug combinations in cancer treatment. We show drug combinations inhibit the growth of multiple tumor models but fails against B16F10. We identify GSDME-mediated pyroptosis triggered by drugs as the critical switch: GSDME mediated pyroptosis drives CCL5 release, recruiting dendritic cells (DCs) and CD8⁺ T cells to initiate adaptive immunity. B16F10 cells express minimal GSDME and therefore undergo apoptosis to retain CCL5 intracellular and abrogating antitumor immunity. Overexpression of GSDME in B16F10 restores pyroptosis, CCL5 secretion, and treatment sensitivity, while GSDME loss abolishes efficacy in responsive models. Notably, pyroptosis in GSDME-proficient subsets propagates systemic immunity, controlling distant GSDME-deficient lesions. In human cancers, GSDME expression correlates with CD8⁺ T cell and DC infiltration. High GSDME predicts superior survival in BTZ-treated multiple myeloma patients. These findings establish GSDME mediated pyroptosis as the primary route for CCL5 secretion, explaining differential efficacy across tumor models and suggesting patients with high GSDME expression may benefits more from proteasome inhibitor-based therapies.
Insights
Gasdermin E (GSDME)-mediated pyroptosis is crucial for proteasome inhibitor efficacy. This cell death pathway drives immune cell recruitment, enhancing antitumor responses and improving patient survival in certain cancers.
Area of Science:
- Oncology
- Immunology
- Cell Death Mechanisms
Background:
- Proteasome inhibitors have limited efficacy in solid tumors.
- Previous studies showed Bortezomib combinations inhibit breast cancer growth via the immune system.
Purpose of the Study:
- To explore the broad application of Bortezomib drug combinations in cancer treatment.
- To identify the mechanism underlying differential efficacy of these drug combinations across tumor models.
Main Methods:
- Utilized multiple tumor models to assess drug combination efficacy.
- Investigated Gasdermin E (GSDME)-mediated pyroptosis as a key mechanism.
- Analyzed CCL5 secretion, immune cell recruitment (dendritic cells and CD8+ T cells), and GSDME expression in tumor cells and human cancers.
Main Results:
- Drug combinations inhibited multiple tumor models but failed in B16F10 melanoma.
- GSDME-mediated pyroptosis was identified as the critical switch, driving CCL5 release and immune recruitment.
- B16F10 cells with low GSDME underwent apoptosis, abrogating antitumor immunity.
- Overexpressing GSDME restored pyroptosis and treatment sensitivity; GSDME loss abolished efficacy.
- Pyroptosis in GSDME-proficient tumors promoted systemic immunity against distant GSDME-deficient lesions.
- Human cancer GSDME expression correlated with CD8+ T cell and dendritic cell infiltration.
- High GSDME expression predicted superior survival in Bortezomib-treated multiple myeloma patients.
Conclusions:
- GSDME-mediated pyroptosis is the primary route for CCL5 secretion, explaining differential drug efficacy.
- GSDME expression levels dictate sensitivity to proteasome inhibitor-based therapies.
- Patients with high GSDME expression may benefit more from these treatments, particularly in multiple myeloma.
