Ubiquitin ligases Siah1a/2 control alveolar macrophage functions to limit carcinogen-induced lung adenocarcinoma.

Cellular components of the tumor microenvironment, including myeloid cells, play important roles in the progression of lung adenocarcinoma (LUAD) and its response to therapy. Here, we characterize the function of the ubiquitin ligases Siah1a/2 in regulating the differentiation and activity of alveolar macrophages (AMs) and assess the implication of Siah1a/2 control of AMs for carcinogen-induced LUAD. Macrophage-specific genetic ablation of Siah1a/2 promoted accumulation of AMs with an immature phenotype and increased expression of pro-tumorigenic and pro-inflammatory Stat3 and β-catenin gene signatures. Administration of urethane to wild-type mice promoted enrichment of immature-like AMs and lung tumor development, which was enhanced by macrophage-specific Siah1a/2 ablation. The pro-fibrotic gene signature seen in Siah1a/2-ablated immature-like macrophages was associated with increased tumor infiltration of CD14+ myeloid cells and poorer survival of LUAD patients. Single-cell RNA-seq confirmed the presence of a cluster of immature-like AMs expressing a pro-fibrotic signature in lungs of LUAD patients, a signature enhanced in smokers. These findings identify Siah1a/2 in alveolar macrophages as gatekeepers of lung cancer development.