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Peer-reviewedCC BY-NCScience Advances

Tumor gasdermin E acts as a rheostat to limit apoptotic cell survival and mutagenesis in anticancer immune environments

  • Beiyun C. Liu1
  • Suresh Poudel1
  • Xiaoyu M. Zhang1
  • Mark J. Chen2
  • Quang Tran3
  • Cliff Guy1
  • Mao Yang1
  • Heather Mulder4
  • Xiaotu Ma4
  • Douglas R. Green1
4 affiliations
  1. 1Department of Immunology, Comprehensive Cancer Center, St. Jude Children’s Research Hospital, Memphis, TN, USA.
  2. 2Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA.
  3. 3Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  4. 4Department of Computational Biology, Comprehensive Cancer Center, St. Jude Children’s Research Hospital, Memphis, TN, USA.
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Abstract

Recent studies have described an ability of cancer cells to survive engagement of apoptotic pathways following chemical and therapeutic insults, challenging the prevailing model that caspase activation inevitably leads to cellular demise. Gasdermin E (GSDME), whose expression is frequently down-regulated or silenced in many tumors and tumor-derived cell lines, is a putative tumor suppressor capable of facilitating the induction of antitumor immunity. We found that GSDME expression precluded high caspase activity before cellular membrane rupture downstream of chemical and immune-mediated insults, and its absence allowed for enhanced activities downstream of caspase activation, including the DNA-damaging effects of caspase-activated deoxyribonuclease. Loss of GSDME allowed cells that had sustained DNA damage to survive, resulting in development and propagation of mutated clones. We conclude that GSDME functions as a key rheostat for determining cell death outcomes by tuning the tolerance to the activities of caspases and their substrates during apoptosis. In analyzing solid tumors in The Cancer Genome Atlas, we found that tumor mutational burden was higher in tumors with low GSDME expression and high immune signatures, supporting the possibility that the effects we describe affect tumor mutation in response to immune assault.

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Cite

BibTeXRIS
BibTeX
@article{liu2026tumor,
  title = {{Tumor gasdermin E acts as a rheostat to limit apoptotic cell survival and mutagenesis in anticancer immune environments}},
  author = {Beiyun C. Liu and Suresh Poudel and Xiaoyu M. Zhang and Mark J. Chen and Quang Tran and Cliff Guy and Mao Yang and Heather Mulder and Xiaotu Ma and Douglas R. Green},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeb1137},
  url = {https://www.science.org/doi/10.1126/sciadv.aeb1137},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Tumor gasdermin E acts as a rheostat to limit apoptotic cell survival and mutagenesis in anticancer immune environments
AU  - Beiyun C. Liu
AU  - Suresh Poudel
AU  - Xiaoyu M. Zhang
AU  - Mark J. Chen
AU  - Quang Tran
AU  - Cliff Guy
AU  - Mao Yang
AU  - Heather Mulder
AU  - Xiaotu Ma
AU  - Douglas R. Green
PY  - 2026
DA  - 2026/10/02
JO  - Science Advances
DO  - 10.1126/sciadv.aeb1137
UR  - https://www.science.org/doi/10.1126/sciadv.aeb1137
AB  - Recent studies have described an ability of cancer cells to survive engagement of apoptotic pathways following chemical and therapeutic insults, challenging the prevailing model that caspase activation inevitably leads to cellular demise. Gasdermin E (GSDME), whose expression is frequently down-regulated or silenced in many tumors and tumor-derived cell lines, is a putative tumor suppressor capable of facilitating the induction of antitumor immunity. We found that GSDME expression precluded high caspase activity before cellular membrane rupture downstream of chemical and immune-mediated insults, and its absence allowed for enhanced activities downstream of caspase activation, including the DNA-damaging effects of caspase-activated deoxyribonuclease. Loss of GSDME allowed cells that had sustained DNA damage to survive, resulting in development and propagation of mutated clones. We conclude that GSDME functions as a key rheostat for determining cell death outcomes by tuning the tolerance to the activities of caspases and their substrates during apoptosis. In analyzing solid tumors in The Cancer Genome Atlas, we found that tumor mutational burden was higher in tumors with low GSDME expression and high immune signatures, supporting the possibility that the effects we describe affect tumor mutation in response to immune assault.
SN  - 2375-2548
ER  -