Nanotoxin induces in situ pyroptosis to sensitize aPD1 to ablate metastases in microsattellite stable colorectal cancer
Por:
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
Publicada:
1 nov 2025
Ahead of Print:
1 oct 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-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.
Filiaciones:
Carrasco-Díaz, LM:
Inst Recerca St Pau IR SANT PAU, St Quinti 77-79, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst IJC St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Bellaterra, Spain
Otero-Mateo, M:
Inst Recerca St Pau IR SANT PAU, St Quinti 77-79, Barcelona 08041, Spain
Alamo, P:
Inst Recerca St Pau IR SANT PAU, St Quinti 77-79, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst IJC St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Bellaterra, Spain
Gallardo, A:
Hosp Santa Creu & Sant Pau, Dept Pathol, Barcelona 08041, Spain
Virgili, AC:
Inst Recerca St Pau IR SANT PAU, St Quinti 77-79, Barcelona 08041, Spain
Hosp Santa Creu & Sant Pau, Dept Med Oncol, Barcelona 08041, Spain
Páez, D:
Hosp Santa Creu & Sant Pau, Dept Med Oncol, Barcelona 08041, Spain
CIBER Enfermedades Raras CIBERER, Barcelona, Spain
Voltà-Durán, E:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Bellaterra, Spain
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Bellaterra 08193, Spain
Villaverde, A:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Bellaterra, Spain
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Bellaterra 08193, Spain
Univ Autonoma Barcelona, Dept Gene & Microbiol, Bellaterra 08193, Spain
Vázquez, E:
CIBER Bioingn Biomat & Nanomed CIBER BBN, Bellaterra, Spain
Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Bellaterra 08193, Spain
Univ Autonoma Barcelona, Dept Gene & Microbiol, Bellaterra 08193, Spain
Unzueta, U:
Inst Recerca St Pau IR SANT PAU, St Quinti 77-79, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst IJC St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Bellaterra, Spain
Univ Autonoma Barcelona, Dept Gene & Microbiol, Bellaterra 08193, Spain
Casanova, I:
Inst Recerca St Pau IR SANT PAU, St Quinti 77-79, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst IJC St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Bellaterra, Spain
Alba-Castellon, L:
Inst Recerca St Pau IR SANT PAU, St Quinti 77-79, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst IJC St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Bellaterra, Spain
Mangues, R:
Inst Recerca St Pau IR SANT PAU, St Quinti 77-79, Barcelona 08041, Spain
Josep Carreras Leukaemia Res Inst IJC St Pau, Barcelona, Spain
CIBER Bioingn Biomat & Nanomed CIBER BBN, Bellaterra, Spain
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