Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity
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.
Authors
- Pietro Fontana (ORCID: https://orcid.org/0000-0003-3215-3784)
- Judy Lieberman (ORCID: https://orcid.org/0000-0002-6200-4715)
- Judith Agudo (ORCID: https://orcid.org/0000-0002-3576-3169)
- Hao Wu (ORCID: https://orcid.org/0000-0002-7281-8579)
- Pilar Baldominos (ORCID: https://orcid.org/0000-0002-4988-6290)
- Liam B. Healy (ORCID: https://orcid.org/0000-0002-2640-1596)
- Jun Hu (ORCID: https://orcid.org/0000-0001-7098-6272)
- Ahmet Buğra Tufan (ORCID: https://orcid.org/0000-0002-8734-9736)
- Zhouyihan Li
- Setu M. Vora
- Dian-Jang Lee (ORCID: https://orcid.org/0000-0001-7268-3240)
- Ming Shi (ORCID: https://orcid.org/0000-0003-0527-0061)
- Hongbo R. Luo (ORCID: https://orcid.org/0000-0002-8545-0451)
- Shiyu Xia (ORCID: https://orcid.org/0000-0001-9024-0689)
- Ying Zhang
- Gang Du
- Haiwei Zhang
- Heng Ru
Institutions
- Boston Children's Hospital (US)
- Harvard University (US)
- Peking University (CN)
- Dana-Farber Cancer Institute (US)
- Cellular Research (United States) (US)
- Center for Life Sciences (CN)
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
Publication Details
- Journal
- Cell
- Published
- 2024-09-06
- DOI
- https://doi.org/10.1016/j.cell.2024.08.007
- Citations
- 79
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 18.47
Funders
- Cancer Research Institute
- Boston Children's Hospital
- Deutsche Forschungsgemeinschaft
- National Institutes of Health