Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis

Highlights•Embryo-derived alveolar macrophages (AMs) induce disseminated cancer cell dormancy•Disseminated cancer cells (DCCs) interact frequently with AMs in the lung alveolus•DCC dormancy is due to persistent AM-DCC interactions via TGF-β2-TGF-βRIII signaling•Loss of AMs or TGF-βRIII in DCCs eliminates an innate immune barrier to metastasisSummaryBreast disseminated cancer cells (DCCs) can remain dormant in the lungs for extended periods, but the mechanisms limiting their expansion are not well understood. Research indicates that tissue-resident alveolar macrophages suppress breast cancer metastasis in lung alveoli by inducing dormancy. Through ligand-receptor mapping and intravital imaging, it was found that alveolar macrophages express transforming growth factor (TGF)-β2. This expression, along with persistent macrophage-cancer cell interactions via the TGF-βRIII receptor, maintains cancer cells in a dormant state. Depleting alveolar macrophages or losing the TGF-β2 receptor in cancer cells triggers metastatic awakening. Aggressive breast cancer cells are either suppressed by alveolar macrophages or evade this suppression by avoiding interaction and downregulating the TGF-β2 receptor. Restoring TGF-βRIII in aggressive cells reinstates TGF-β2-mediated macrophage growth suppression. Thus, alveolar macrophages act as a metastasis immune barrier, and downregulation of TGF-β2 signaling allows cancer cells to overcome macrophage-mediated growth suppression.Graphical abstract