| First Author | Fontana P | Year | 2024 |
| Journal | Cell | Volume | 187 |
| Issue | 22 | Pages | 6165-6181.e22 |
| PubMed ID | 39243763 | Mgi Jnum | J:358179 |
| Mgi Id | MGI:7779302 | Doi | 10.1016/j.cell.2024.08.007 |
| Citation | Fontana P, et al. (2024) Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity. Cell 187(22):6165-6181.e22 |
| abstractText | 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. |
