Unbiased niche labeling maps immune-excluded niche in bone metastasis

Microenvironment niches determine cellular fates of metastatic cancer cells. However, robust and unbiased approaches to identify niche components and their molecular profiles are lacking. We established Sortase A-Based Microenvironment Niche Tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastatic colonization. SAMENT was applied to multiple cancer models colonizing the same organ and the same cancer to different organs. Common niche features include macrophage enrichment and T cell depletion. Macrophage niches are phenotypically diverse in different organs. In bone, niche macrophages express estrogen receptor (ER) and exhibit active ER signaling in male and female hosts. Conditional knockout of ER in macrophages significantly retarded bone colonization by allowing T cell infiltration. ER expression was also discovered in human bone metastases of both genders. Collectively, we identified a unique population of ER+ macrophages in metastatic niche and functionally tie ER signaling in macrophages to T cell exclusion during metastatic colonization.