Language

English

Publication Date

5-28-2026

Journal

Cell

DOI

10.1016/j.cell.2026.04.009

PMID

42054994

PMCID

PMC13235847

PubMedCentral® Posted Date

6-5-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Metastatic cancer cell fate is shaped by the local microenvironment niches. To unbiasedly define the cellular and molecular features of metastatic niches, we developed sortase A-based microenvironment niche tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastasis. Applying SAMENT across multiple cancer models and target organs revealed shared niche features, including macrophage enrichment and T cell depletion, alongside marked organ-specific phenotype heterogeneity in niche macrophages. In bone, metastatic niches are enriched for macrophages expressing estrogen receptor alpha (ERα) with active ERα signaling. Conditional deletion of Esr1 in macrophages significantly impaired bone colonization by enabling T cell infiltration. ERα⁺ macrophages were also identified in human bone metastases across multiple cancer types. Together, these findings define a distinct ERα⁺ macrophage niche and establish macrophage ERα signaling as a key driver of T cell exclusion during metastatic colonization.

Keywords

Animals, Humans, Estrogen Receptor alpha, Macrophages, Bone Neoplasms, Tumor Microenvironment, Mice, Female, Signal Transduction, T-Lymphocytes, Cysteine Endopeptidases, Aminoacyltransferases, Neoplasm Metastasis, Bacterial Proteins

Published Open-Access

yes

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