Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity
Pietro Fontana, Gang Du, Ying Zhang, Haiwei Zhang, Setu M. Vora, Jun Hu, Ming Shi, Ahmet Buğra Tufan, Liam B. Healy, Shiyu Xia, Dian-Jang Lee, Zhouyihan Li, Pilar Baldominos, Heng Ru, Hongbo R. Luo, Judith Agudo, Judy Lieberman, Hao Wu
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.