Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer

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 (CXC...

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Autores: Carrasco-Díaz, LM, Otero-Mateo, M, Alamo, P, Gallardo, A, Virgili, AC, Páez, D, Voltà-Durán, E, Villaverde, A, Vázquez, E, Unzueta, U, Casanova, I, Alba-Castellon, L, Mangues, R
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p20424
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=20424
Access Level:acceso abierto
Palabra clave:Targeted nanotoxin
In situ release
Pyroptosis
T cell recruitment
Antimetastatic effect
Immuno-oncology
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spelling Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancerCarrasco-Díaz, LMOtero-Mateo, MAlamo, PGallardo, AVirgili, ACPáez, DVoltà-Durán, EVillaverde, AVázquez, EUnzueta, UCasanova, IAlba-Castellon, LMangues, RTargeted nanotoxinIn situ releasePyroptosisT cell recruitmentAntimetastatic effectImmuno-oncologyNanomedicine 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-1 beta. 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 alpha PD1 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 alpha PD1 enhances T cell activation, reaching a synergistic response in MSS CRC models.ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=20424PHARMACOLOGICAL RESEARCHISSN: 10436618ISSNe: 10961186reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p204242026-06-14T12:41:47Z
dc.title.none.fl_str_mv Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer
title Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer
spellingShingle Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer
Carrasco-Díaz, LM
Targeted nanotoxin
In situ release
Pyroptosis
T cell recruitment
Antimetastatic effect
Immuno-oncology
title_short Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer
title_full Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer
title_fullStr Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer
title_full_unstemmed Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer
title_sort Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer
dc.creator.none.fl_str_mv Carrasco-Díaz, LM
Otero-Mateo, M
Alamo, P
Gallardo, A
Virgili, AC
Páez, D
Voltà-Durán, E
Villaverde, A
Vázquez, E
Unzueta, U
Casanova, I
Alba-Castellon, L
Mangues, R
author Carrasco-Díaz, LM
author_facet Carrasco-Díaz, LM
Otero-Mateo, M
Alamo, P
Gallardo, A
Virgili, AC
Páez, D
Voltà-Durán, E
Villaverde, A
Vázquez, E
Unzueta, U
Casanova, I
Alba-Castellon, L
Mangues, R
author_role author
author2 Otero-Mateo, M
Alamo, P
Gallardo, A
Virgili, AC
Páez, D
Voltà-Durán, E
Villaverde, A
Vázquez, E
Unzueta, U
Casanova, I
Alba-Castellon, L
Mangues, R
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Targeted nanotoxin
In situ release
Pyroptosis
T cell recruitment
Antimetastatic effect
Immuno-oncology
topic Targeted nanotoxin
In situ release
Pyroptosis
T cell recruitment
Antimetastatic effect
Immuno-oncology
description 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-1 beta. 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 alpha PD1 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 alpha PD1 enhances T cell activation, reaching a synergistic response in MSS CRC models.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=20424
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=20424
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
publisher.none.fl_str_mv ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
dc.source.none.fl_str_mv PHARMACOLOGICAL RESEARCH
ISSN: 10436618
ISSNe: 10961186
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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