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| Página principal > Artículos > Artículos publicados > Nanotoxin induces in situ pyroptosis to sensitize αPD1 to ablate metastases in microsattellite stable colorectal cancer |
(Institut de Recerca Sant Pau) (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya)) (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya)) (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya)) (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí") (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia) (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí") (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia) (Institut de Recerca Sant Pau) (Institut de Recerca Sant Pau) (Institut de Recerca Sant Pau)
| Fecha: | 2025 |
| Resumen: | 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. |
| Ayudas: | Instituto de Salud Carlos III PI24/01476 Instituto de Salud Carlos III PI21/00150 Instituto de Salud Carlos III PI20/00400 Instituto de Salud Carlos III PI24/00012 Instituto de Salud Carlos III PI23/00318 Instituto de Salud Carlos III FI19/00148 Instituto de Salud Carlos III CP19/00028 Instituto de Salud Carlos III CP24/00111 Agencia Estatal de Investigación PID2020-116174RB-I00 Agencia Estatal de Investigación PID2019–105416RB-I00 Agencia Estatal de Investigación PDC2022–133858-I00 Agencia Estatal de Investigación PID2022–1368450OB-I00 Agencia Estatal de Investigación FPU18/04615 Ministerio de Sanidad y Consumo CB06/01/1031 Generalitat de Catalunya 2017/SGR-865 Generalitat de Catalunya 2021/SGR-01140 Ministerio de Sanidad y Consumo CB06/01/1014 Generalitat de Catalunya 2017/SGR-229 |
| Nota: | Altres ajuts: The European Union, got support to run the EU COST Action CA17140 and CA21135 |
| Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Lengua: | Anglès |
| Documento: | Article de revisió ; recerca ; Versió publicada |
| Materia: | Targeted nanotoxin ; In situ release ; Pyroptosis ; T cell recruitment ; Antimetastatic effect ; Immuno-oncology |
| Publicado en: | Pharmacological research, Vol. 221 (November 2025) , art. 107982, ISSN 1096-1186 |
