New article: "Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer"

Abstract:

Nanomedicine has not generated anticancer immunotherapies because of insufficient targeted specificity, lack of immunity, and associated toxicity. We developed a T22-DITOX-H6 (TDX) nanotoxin to selectively release the diphtheria toxin in the cancer cells in immunosuppressed CXCR4-overexpressing (CXCR4+) colorectal (CRC) models, inducing pyroptosis and anticancer effect.

Microsatellite stable (MSS) CRC patients do not respond to current immunotherapy. Since pyroptosis is highly immunogenic, we treated with TDX immunocompetent CXCR4+CT26 MSS metastatic CRC models to selectively deliver the toxin to induce in situ pyroptosis mediated by the activation of NLRP3, Caspase-1 GSDMD and IL-1β. In contrast to immunosuppressed, in situ pyroptosis by TDX in immunocompetent models trigger CD8+T cell recruitment, activation and killing of cancer cells in tissues, mimicking the pyroptosis that the host induces to kill diphtheria-infected cells.

The combination of TDX and αPD1 further increases CD8+ recruitment and perforin secretion, achieving a tissue-specific antimetastatic activity in mesentery, peritoneum, and lung, and especially in liver metastases, without systemic toxicity. This is the first time that a novel nanomedicine achieves local T cell activation and antimetastatic effect mediated by pyroptosis and immunogenic cell death, whereas the combination with αPD1 enhances T cell activation, reaching a synergistic response in MSS CRC models.

Article data:

Luis M. Carrasco-Díaz, Marc Otero-Mateo, Patricia Álamo, Alberto Gallardo, Anna C. Virgili, David Páez, Eric Voltà-Durán, Antonio Villaverde, Esther Vázquez, Ugutz Unzueta, Isolda Casanova, Lorena Alba-Castellon, Ramon Mangues. Nanotoxin induces in situ pyroptosis to sensitize αPD1 to ablate metastases in microsattellite stable colorectal cancer. Pharmacological Research, Volume 221, 2025,107982, ISSN 1043-6618.

DOI: 10.1016/j.phrs.2025.107982.