2. Academic Validation
  3. Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer

Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer

  • Sci Transl Med. 2023 Nov;15(720):eadg3049. doi: 10.1126/scitranslmed.adg3049.
Jingbo Li 1 2,  Jiao Liu 3,  Zhuan Zhou 2,  Runliu Wu 2,  Xin Chen 2,  Chunhua Yu 2,  Brent Stockwell 4,  Guido Kroemer 5 6 7,  Rui Kang 2,  Daolin Tang 2
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
  • 2 Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3 DAMP Laboratory, Third Affiliated Hospital, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou, Guangdong 510510, China.
  • 4 Department of Chemistry, Columbia University, New York, NY 10027, USA.
  • 5 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris Cité, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France.
  • 6 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, 94800 Villejuif, France.
  • 7 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, F-75015 Paris, France.
PMID: 37910602 DOI: 10.1126/scitranslmed.adg3049
Abstract

Lipid peroxidation-dependent Ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce Ferroptosis in malignant cells but also trigger Ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a Ferroptosis inducer that triggered the degradation of Glutathione Peroxidase 4 (GPX4), a key Ferroptosis repressor, specifically in Cancer cells. N6F11 did not cause the degradation of GPX4 in immune cells, including dendritic, T, natural killer, and neutrophil cells. Mechanistically, N6F11 bound to the RING domain of E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) in Cancer cells to trigger TRIM25-mediated K48-linked ubiquitination of GPX4, resulting in its proteasomal degradation. Functionally, N6F11 treatment caused ferroptotic Cancer cell death that initiated HMGB1-dependent antitumor immunity mediated by CD8+ T cells. N6F11 also sensitized immune checkpoint blockade that targeted CD274/PD-L1 in advanced Cancer models, including genetically engineered mouse models of pancreatic Cancer driven by KRAS and TP53 mutations. These findings may establish a safe and efficient strategy to boost ferroptosis-driven antitumor immunity.

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