Gasdermin E
Gasdermin E
Overview
Gasdermin E (GSDME), also known as DFNA5, is a pore-forming protein in the gasdermin family that is best known for its role in regulated cell death. In many biological contexts, GSDME is cleaved by active cysteine-aspartic acid protease 3 (caspase-3), releasing an N-terminal fragment that can disrupt the plasma membrane and drive pyroptosis, a lytic and highly inflammatory form of cell death. This places GSDME at the intersection of apoptosis and pyroptosis, where it can convert a caspase-3–mediated apoptotic signal into membrane rupture, cytokine release, and immunogenic cell death.
Because of this switch-like function, GSDME has attracted substantial interest in cancer biology and therapeutic development. In tumor settings, activation of the caspase-3/GSDME axis has been explored as a way to overcome apoptosis resistance and promote antitumor immunity. Recent studies have linked GSDME-dependent pyroptosis with enhanced release of proinflammatory cytokines, increased antigen presentation, and improved immune-cell recruitment, including CD8+ T cells, often in combination with checkpoint inhibitor strategies such as anti-PD-1/PD-L1 or anti-CTLA-4 therapy.
Focus of Latest Publications
Recent publications have focused on Gasdermin E (GSDME) as a key executioner of pyroptosis in cancer therapy, particularly in strategies designed to overcome resistance to apoptosis and enhance antitumor immunity. Across these studies, GSDME was activated downstream of caspase-3 in response to diverse interventions, including phototherapy, chemodynamic therapy, drug repurposing, and immune-checkpoint-related signaling modulation. The common theme was that GSDME-mediated membrane permeabilization and inflammatory cell death could convert tumor cells into sources of immunostimulatory signals, thereby improving immune recognition and therapeutic response in Malignant Disease.
Several nanomedicine-based studies used GSDME as a mechanistic endpoint for inducing pyroptosis under controlled subcellular or tumor microenvironment conditions. A mitochondria-targeted zwitterionic nanogel platform triggered reactive oxygen species amplification after 640 nm laser irradiation, activating the caspase-3/GSDME pyroptosis pathway and producing strong tumor inhibition with minimal systemic toxicity. Similarly, a manganese vacancy-engineered Prussian blue derivative enabled 1060 nm photoimmunotherapy, where excessive ROS induced GSDME-mediated pyroptosis, promoted mitochondrial DNA release, and cooperated with Mn2+ to activate the cGAS-STING pathway. In a composite nanovesicle system, β-lapachone, Mn2+, and decitabine were co-delivered to amplify ROS, induce mitochondrial damage, and trigger caspase-3 cleavage of GSDME; decitabine further restored GSDME expression by DNA demethylation, strengthening pyroptosis and antitumor immune activation.
Other studies identified pharmacologic and signaling-based routes to GSDME-dependent pyroptosis. Saquinavir was shown to inhibit hepatocellular carcinoma cell growth by triggering caspase-3/GSDME-dependent pyroptosis, in part through suppression of glucose metabolism, ROS outburst, and targeting of OTUD5, which promoted JAK1 degradation and mitochondrial disruption. In anti-PD-1-refractory tumors, pan-PKC inhibition overcame immune resistance by inducing caspase-3/GSDME-dependent immunogenic pyroptotic cell death, alongside enhanced CD8+ T cell recruitment and effector function. These findings linked GSDME activation not only to direct tumor cell killing but also to broader immune remodeling, including improved checkpoint inhibitor responsiveness.
Review articles in this set further emphasized GSDME as a central node in the apoptosis-pyroptosis transition. They highlighted the caspase-3/GSDME axis as a major molecular switch that can redirect apoptotic signaling toward inflammatory pyroptosis, especially in apoptosis-resistant tumors. Collectively, these publications position Gasdermin E as an important therapeutic target and effector in cancer strategies aimed at inducing pyroptosis, amplifying innate immune signaling, and improving the efficacy of checkpoint inhibitor-based combinations.