Gasdermin-Mediated Cell Death in Tumor Microenvironments

Gasdermin-mediated programmed cell death, commonly termed pyroptosis, has emerged as a pivotal mechanism shaping the immune and inflammatory landscape of the tumour microenvironment. Members of the gasdermin family (GSDMA–GSDME) undergo proteolytic activation to release an N-terminal fragment that oligomerises to form membrane pores. These pores not only compromise cell integrity, leading to lytic death of malignant or stromal cells, but also permit the release of proinflammatory mediators and damage-associated molecular patterns. In solid tumours, pyroptosis can exert dual roles: on one hand, it may amplify anti-tumour immunity by recruiting cytotoxic lymphocytes and myeloid effectors; on the other, excessive or dysregulated gasdermin activation can foster chronic inflammation, angiogenesis and immunosuppression. Recent advances have highlighted the influence of metabolic cues, redox status and death-receptor signalling in modulating gasdermin cleavage by caspases or other proteases. The spatiotemporal balance between tumour-cell pyroptosis and pyroptosis of infiltrating immune cells underpins treatment outcomes in chemotherapy, radiotherapy and emerging immunotherapies. Unravelling the molecular determinants that govern gasdermin pore formation and its downstream inflammatory cascade offers promising avenues for therapeutic intervention and biomarker development.

Research from Nature Portfolio

Recent structural and mechanistic studies have provided deep insight into gasdermin regulation. A high-resolution crystal structure of human GSDMB in complex with a bacterial E3 ubiquitin ligase has revealed key membrane-engagement loops and ubiquitination sites that control N-terminal fragment release and pore assembly. This work elucidates how post-translational modification of gasdermins can be co-opted by intracellular pathogens and, by extension, suggests analogous regulatory circuits in tumour cells. Understanding these interactions establishes a framework to design specific inhibitors or stabilisers of gasdermin pore formation, with potential to fine-tune pyroptotic signalling in cancer therapy.

Gasdermin-Mediated Cell Death in Tumor Microenvironments publication trend

The graph below shows the total number of articles in gasdermin-mediated cell death in tumor microenvironments across all publications each year (not limited to Nature Index journals).

Technical terms

Pyroptosis: A form of lytic programmed cell death characterised by gasdermin-mediated pore formation and release of proinflammatory intracellular contents.

Gasdermin: A family of pore-forming proteins (GSDMA–GSDME) with an autoinhibited C-terminal domain and a cytotoxic N-terminal domain released upon proteolysis.

Tumour microenvironment: The complex milieu surrounding tumour cells, comprising stromal cells, immune infiltrates, extracellular matrix and soluble mediators that influence cancer progression.

Receptosome: A specialised intracellular platform, often associated with endocytosed death receptors, that recruits proteases and substrates to coordinate regulated cell death pathways.

References

1. Insights into the GSDMB-mediated cellular lysis and its targeting by IpaH7.8. Nature Communications (2023).
2. The metabolite α-KG induces GSDMC-dependent pyroptosis through death receptor 6-activated caspase-8. Cell Research (2021).
3. HMGB1 released from GSDME-mediated pyroptotic epithelial cells participates in the tumorigenesis of colitis-associated colorectal cancer through the ERK1/2 pathway. Journal of Hematology & Oncology (2020).