New research challenges the established role of Gasdermin E (GSDME) as a pyroptosis executor by demonstrating its paradoxical contribution to glioblastoma’s resistance to pyroptosis and tumor progression. The study revealed altered post-translational modifications and spatial distribution of GSDME in glioblastoma cells, which prevent pyroptotic cleavage events despite aggressive tumor behavior. These insights reshape understanding of glioblastoma biology and highlight GSDME as a multifaceted target for developing novel therapeutic strategies against this lethal brain cancer.