| First Author | Duval F | Year | 2025 |
| Journal | iScience | Volume | 28 |
| Issue | 5 | Pages | 112498 |
| PubMed ID | 40475851 | Mgi Jnum | J:367540 |
| Mgi Id | MGI:8210350 | Doi | 10.1016/j.isci.2025.112498 |
| Citation | Duval F, et al. (2025) Trajectories of macrophage ontogeny and reprogramming in cancer. iScience 28(5):112498 |
| abstractText | Tumor-associated macrophages (TAMs) often manifest immunosuppressive and tumor-promoting phenotypes contributing to immunotherapy resistance. Dicer1 inactivation in TAMs (D(KO)) prompts their immunostimulatory activation, enabling effective immunotherapy in mouse cancer models. Single-cell RNA sequencing (scRNA-seq) analysis revealed interferon-gamma (IFNgamma)-dependent immunostimulatory programming of the tumor microenvironment in D(KO) mice. In tumors of wild-type mice and patients with cancer, dynamic inferences on macrophage ontogeny by pseudotime analysis identified trajectories associated with monocyte-to-macrophage differentiation, progression into the cell cycle, and transition from immunostimulatory (M1-like) to immunosuppressive and protumoral (M2-like) states. Dicer1 inactivation interfered with this trajectory and stalled TAMs at an intermediate state, impeding immunosuppressive and M2-like TAM development. This reprogramming translated into enhanced response to antiangiogenic immunotherapy in an orthotopic lung cancer model. Cycling/M2-like macrophages are conserved in mouse and human cancers and are enriched in patients with poor response to immunotherapy, making them a more selective therapeutic target than the bulk of TAMs. |
