In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation

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 and Mario Leonardo Squadrito ()
Additional contact information
Marco Notaro: IRCCS San Raffaele Scientific Institute
Maristella Borghetti: IRCCS San Raffaele Scientific Institute
Chiara Bresesti: IRCCS San Raffaele Scientific Institute
Giovanna Giacca: IRCCS San Raffaele Scientific Institute
Thomas Kerzel: IRCCS San Raffaele Scientific Institute
Carl Mirko Mercado: IRCCS San Raffaele Scientific Institute
Stefano Beretta: IRCCS San Raffaele Scientific Institute
Marco Monti: IRCCS San Raffaele Scientific Institute
Ivan Merelli: IRCCS San Raffaele Scientific Institute
Silvia Iaia: IRCCS San Raffaele Scientific Institute
Marco Genua: IRCCS San Raffaele Scientific Institute
Andrea Annoni: IRCCS San Raffaele Scientific Institute
Tamara Canu: IRCCS San Raffaele Scientific Institute
Patrizia Cristofori: IRCCS San Raffaele Scientific Institute
Sara Degl’Innocenti: IRCCS San Raffaele Scientific Institute
Francesca Sanvito: IRCCS San Raffaele Scientific Institute
Paola Maria Vittoria Rancoita: Vita-Salute San Raffaele University
Renato Ostuni: Vita-Salute San Raffaele University
Silvia Gregori: IRCCS San Raffaele Scientific Institute
Luigi Naldini: Vita-Salute San Raffaele University
Mario Leonardo Squadrito: IRCCS San Raffaele Scientific Institute

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58369-2

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