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@ARTICLE{Enssle:301318,
      author       = {S. Enssle and A. Sax and P. May and N. El Khawanky and N.
                      Soliman and M. Perl and J. C. Enssle and K. Krey and J.
                      Ruland$^*$ and A. Pichlmair and F. Bassermann$^*$ and H.
                      Poeck and S. Heidegger},
      title        = {{G}asdermin {E} links tumor cell-intrinsic nucleic acid
                      signaling to proinflammatory cell death for successful
                      checkpoint inhibitor cancer immunotherapy.},
      journal      = {OncoImmunology},
      volume       = {14},
      number       = {1},
      issn         = {2162-4011},
      address      = {Abingdon},
      publisher    = {Taylor $\&$ Franics},
      reportid     = {DKFZ-2025-00990},
      pages        = {2504244},
      year         = {2025},
      abstract     = {Durable clinical responses to immune checkpoint inhibitors
                      (ICI) are limited to a minority of patients, and molecular
                      pathways that modulate their efficacy remain incompletely
                      defined. We have recently shown that activation of the
                      innate RNA-sensing receptor RIG-I and associated apoptotic
                      tumor cell death can facilitate tumor immunosurveillance and
                      -therapy, but the mechanism that drives its immunogenicity
                      remained unclear. We here show that intratumoral activity of
                      the pore-forming protein gasdermin E (GSDME) links active
                      RIG-I signaling and apoptotic cell death in tumor cells to
                      inflammatory pyroptosis. Activation of tumor-intrinsic
                      RIG‑I triggered cleavage of GSDME, pore formation, loss of
                      cell membrane integrity and leakage of cytosolic components
                      from dying tumor cells. Tumor antigen cross-presentation by
                      dendritic cells and subsequent expansion of cytotoxic T
                      cells strongly relied on tumor-intrinsic GSDME activity. In
                      preclinical murine cancer models, defective GSDME signaling
                      rendered tumors resistant to ICI therapy. Epigenetic
                      reprogramming with upregulation of Gdsme enhanced the
                      susceptibility of tumor cells to inflammatory cell death and
                      immunotherapy. In humans, transcriptome analysis of melanoma
                      samples showed strong correlation between genetic activity
                      of the RIG-I and pyroptosis pathways. In melanoma patients,
                      high transcriptional activity of a pyroptosis gene set was
                      associated with prolonged survival and beneficial response
                      to ICI therapy. In summary, our data show that GSDME links
                      RIG-I and apoptotic signaling to inflammatory cell death,
                      thereby driving its immunogenicity and responsiveness to
                      ICI. A deeper understanding of these pathways may allow for
                      the development of novel combined modality approaches to
                      improve ICI treatment responses in cancer patients.},
      keywords     = {Humans / Animals / Mice / Signal Transduction / Pyroptosis:
                      immunology / Immune Checkpoint Inhibitors: pharmacology /
                      Immune Checkpoint Inhibitors: therapeutic use /
                      Immunotherapy: methods / DEAD Box Protein 58: metabolism /
                      Cell Line, Tumor / Phosphate-Binding Proteins: metabolism /
                      Melanoma: immunology / Melanoma: pathology / Melanoma:
                      genetics / Melanoma: drug therapy / Female / Gasdermins /
                      Receptors, Immunologic / Cancer immunotherapy (Other) /
                      Gasdermin E (Other) / RIG-I (Other) / apoptosis (Other) /
                      cancer resistance mechanism (Other) / immune checkpoint
                      inhibitors (Other) / immunogenic cell death (Other) /
                      programmed cell death (Other) / pryroptosis (Other) / Immune
                      Checkpoint Inhibitors (NLM Chemicals) / GSDME protein, human
                      (NLM Chemicals) / DEAD Box Protein 58 (NLM Chemicals) /
                      Phosphate-Binding Proteins (NLM Chemicals) / RIGI protein,
                      human (NLM Chemicals) / Gasdermins (NLM Chemicals) /
                      Receptors, Immunologic (NLM Chemicals)},
      cin          = {MU01},
      ddc          = {610},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40366863},
      doi          = {10.1080/2162402X.2025.2504244},
      url          = {https://inrepo02.dkfz.de/record/301318},
}