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

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.

Data availability: The MERFISH, single-cell RNA sequencing and bulk RNA sequencing data have been deposited in the GEO repository under the accession number GSE273615. Additionally, the WES data have been uploaded to the ENA portal with the accession number PRJEB78386.
Code availability: Code is available at the following link: http://www.bioinfotiget.it/gitlab/custom/notaro_mouse_lm_2025.