Niche Labeling Reveals Pro-Metastatic Immune-Cancer Cell Interactions

Cell–cell interactions within the tumor microenvironment have implications for metastasis and treatment response. Existing methods to characterize stable cell–cell interactions lack the ability to detect transient events, prompting Xu, Liu, and colleagues to develop sortase A (SrtA)-based microenvironment niche tagging (SAMENT) to elucidate dynamic cancer cell associations. Introduction of a doxycycline-inducible transgene with a mono-glycine recognition SrtA variant and a GFP nanobody allowed for biotin-dependent, unbiased tagging of cells geographically adjacent to cancer cells. Comparisons of SAMENT with other niche-labeling methods highlighted its sensitivity in labeling cells in close proximity to metastatic cells without requiring strong cell–cell or ligand–receptor binding and its overall spatial and temporal controllability. To understand how cancer cells influence metastatic niches across different organs, lung cancer cells were intracardially injected into mice and SAMENT was utilized to characterize cell associations in the bone, liver, and lungs. Overall, metastatic sites demonstrated a decrease in T cells and an increase in macrophages. Single-cell RNA sequencing of major immune cell types revealed substantial phenotypic diversity of macrophages in areas of cancer cell interaction across organs. Moreover, metastatic niche-associated macrophages showed upregulation of estrogen receptor alpha (ERα) signaling, which was confirmed at the RNA, protein, and activity level. ERα expression was additionally elevated in macrophages from patient samples of bone metastases originating from various primary sites. Further pathway analysis revealed a role for PPARγ-regulated lipid metabolism in fostering an anti-inflammatory, pro-tumor metastatic niche. To determine a causative role for ERα+ macrophages in promoting bone metastasis, Esr1 was conditionally knocked out, resulting in decreased tumor growth across various cancer models in both male and female mice. Additionally, Esr1 knock-out resulted in increased T-cell infiltration, suggesting a role for ERα in mediating immune cell interactions in the bone metastatic niche. Taken together, these data highlight the power of SAMENT to uncover dynamic cell–cell interactions, particularly identifying tumor-promoting ERα signaling in macrophages within the bone metastatic microenvironment.Xu Z, Liu F, Ding Y, Pan T, Wu Y, Han Y, et al. Unbiased niche labeling maps immune-excluded niche in bone metastasis. Cell 2026 Apr 28 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.