Trajectories of macrophage ontogeny and reprogramming in cancer

Tumor-associated macrophages (TAMs) often manifest immunosuppressive and tumor-promoting phenotypes contributing to immunotherapy resistance. <i>Dicer1</i> 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-γ (IFNγ)-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. <i>Dicer1</i> 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.