GSDME mediated pyroptosis drives CCL5 secretion and dictates proteasome inhibitor efficacy in solid tumors.

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.