In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation
Abstract Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regressi...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58369-2 |
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| author | Marco Notaro Maristella Borghetti Chiara Bresesti Giovanna Giacca Thomas Kerzel Carl Mirko Mercado Stefano Beretta Marco Monti Ivan Merelli Silvia Iaia Marco Genua Andrea Annoni Tamara Canu Patrizia Cristofori Sara Degl’Innocenti Francesca Sanvito Paola Maria Vittoria Rancoita Renato Ostuni Silvia Gregori Luigi Naldini Mario Leonardo Squadrito |
| author_facet | Marco Notaro Maristella Borghetti Chiara Bresesti Giovanna Giacca Thomas Kerzel Carl Mirko Mercado Stefano Beretta Marco Monti Ivan Merelli Silvia Iaia Marco Genua Andrea Annoni Tamara Canu Patrizia Cristofori Sara Degl’Innocenti Francesca Sanvito Paola Maria Vittoria Rancoita Renato Ostuni Silvia Gregori Luigi Naldini Mario Leonardo Squadrito |
| author_sort | Marco Notaro |
| collection | DOAJ |
| description | Abstract Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8+ T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4+ T cell help. IFNα and IL-12 produced by armed macrophages reprogram antigen presenting cells and rewire cellular interactions, rescuing tumor reactive T cell functions. In vivo armed macrophages trigger anti-tumor immunity in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases. |
| format | Article |
| id | doaj-art-3192823ab60d481bb6949b7b59cfc444 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3192823ab60d481bb6949b7b59cfc4442025-08-20T02:28:07ZengNature PortfolioNature Communications2041-17232025-04-0116112410.1038/s41467-025-58369-2In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenationMarco Notaro0Maristella Borghetti1Chiara Bresesti2Giovanna Giacca3Thomas Kerzel4Carl Mirko Mercado5Stefano Beretta6Marco Monti7Ivan Merelli8Silvia Iaia9Marco Genua10Andrea Annoni11Tamara Canu12Patrizia Cristofori13Sara Degl’Innocenti14Francesca Sanvito15Paola Maria Vittoria Rancoita16Renato Ostuni17Silvia Gregori18Luigi Naldini19Mario Leonardo Squadrito20Vector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteVector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteVector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteVector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteVector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteVector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteBioInformatics Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteBioInformatics Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteBioInformatics Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteMechanisms of Peripheral Tolerance Unit and Immune Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteGenomics of the Innate Immune System Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteMechanisms of Peripheral Tolerance Unit and Immune Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstitutePreclinical Imaging Facility, IRCCS San Raffaele Scientific InstituteGLP Test Facility, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteGLP Test Facility, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteGLP Test Facility, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteCUSSB University Center for Statistics in the Biomedical Science, Vita-Salute San Raffaele UniversityVita-Salute San Raffaele UniversityMechanisms of Peripheral Tolerance Unit and Immune Core, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteVita-Salute San Raffaele UniversityVector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteAbstract Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8+ T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4+ T cell help. IFNα and IL-12 produced by armed macrophages reprogram antigen presenting cells and rewire cellular interactions, rescuing tumor reactive T cell functions. In vivo armed macrophages trigger anti-tumor immunity in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases.https://doi.org/10.1038/s41467-025-58369-2 |
| spellingShingle | Marco Notaro Maristella Borghetti Chiara Bresesti Giovanna Giacca Thomas Kerzel Carl Mirko Mercado Stefano Beretta Marco Monti Ivan Merelli Silvia Iaia Marco Genua Andrea Annoni Tamara Canu Patrizia Cristofori Sara Degl’Innocenti Francesca Sanvito Paola Maria Vittoria Rancoita Renato Ostuni Silvia Gregori Luigi Naldini Mario Leonardo Squadrito In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation Nature Communications |
| title | In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation |
| title_full | In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation |
| title_fullStr | In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation |
| title_full_unstemmed | In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation |
| title_short | In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation |
| title_sort | in vivo armed macrophages curb liver metastasis through tumor reactive t cell rejuvenation |
| url | https://doi.org/10.1038/s41467-025-58369-2 |
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