2. Academic Validation
  3. Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity

Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity

  • Cell. 2024 Sep 2:S0092-8674(24)00898-5. doi: 10.1016/j.cell.2024.08.007.
Pietro Fontana 1,  Gang Du 1,  Ying Zhang 2,  Haiwei Zhang 3,  Setu M Vora 1,  Jun Jacob Hu 1,  Ming Shi 4,  Ahmet B Tufan 1,  Liam B Healy 1,  Shiyu Xia 1,  Dian-Jang Lee 3,  Zhouyihan Li 3,  Pilar Baldominos 5,  Heng Ru 6,  Hongbo R Luo 7,  Judith Agudo 5,  Judy Lieberman 8,  Hao Wu 9
Affiliations

Affiliations

  • 1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • 2 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
  • 3 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
  • 5 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA 02215, USA.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 7 Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02115, USA; Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 814, Boston, MA 02115, USA.
  • 8 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: judy.lieberman@childrens.harvard.edu.
  • 9 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: wu@crystal.harvard.edu.
PMID: 39243763 DOI: 10.1016/j.cell.2024.08.007
Abstract

Gasdermin-mediated inflammatory cell death (Pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and Pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level Pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated Cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell Pyroptosis to induce antitumor immunity and raise the possibility of exploiting Pyroptosis without causing overt toxicity.

Keywords

GSDMD; GSDMD agonist; antitumor immunity; cancer; checkpoint blockade; gasdermin; immunogenic cell death; immunotherapy; pyroptosis; tumor.

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