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Inflammasome and Immune Disorders · Journal article
Pharmacological Research · August 14, 2026
Encouraging direction, but not yet definitive.
This is a mechanistic study demonstrating that GSDME-mediated pyroptosis, triggered by proteasome inhibitor combinations, drives CCL5 secretion and immune recruitment, explaining differential efficacy across solid tumor models. In human cancers, high GSDME expression correlates with improved survival in bortezomib-treated multiple myeloma and with CD8⁺ T cell infiltration, suggesting GSDME status may predict response to proteasome inhibitor-based therapy.
Preclinical mechanistic study (in vitro and in vivo tumor models) with retrospective correlative analysis of human cancer cohorts. Preclinical: syngeneic tumor models including B16F10 melanoma and other responsive solid tumors. Human: multiple myeloma patients treated with bortezomib and broader human cancer cohorts with available GSDME expression and immune infiltration data. Intervention: Proteasome inhibitor combinations (Bortezomib with ammonium tetrathiomolybdate or AMD3100); GSDME overexpression and knockout in tumor cells. Compared with: Control/vehicle-treated tumors; GSDME-deficient versus GSDME-proficient tumor models.
Drug combinations (Bortezomib with TM or AMD3100) inhibit growth of multiple tumor models but fail against B16F10 cells, which express minimal GSDME and undergo apoptosis instead of pyroptosis GSDME overexpression in B16F10 cells restores pyroptosis, CCL5 secretion, and treatment sensitivity GSDME loss abolishes efficacy in otherwise responsive tumor models
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These findings suggest that GSDME status could be a predictive biomarker for proteasome inhibitor response in solid tumors and multiple myeloma. Patients with high GSDME expression may benefit more from proteasome inhibitor-based therapies, potentially enabling patient stratification in future trials.
Mechanistic study identifying GSDME-mediated pyroptosis as a determinant of proteasome inhibitor efficacy, supported by multiple tumor models and human correlative data, but lacks prospective clinical trials or hard clinical outcomes.
As stated by the source record.
These findings suggest that GSDME status could be a predictive biomarker for proteasome inhibitor response in solid tumors and multiple myeloma. Patients with high GSDME expression may benefit more from proteasome inhibitor-based therapies, potentially enabling patient stratification in future trials.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
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.
Taken from the source record, never inferred. Follow any of these and new work involving them reaches your briefing.