2. Academic Validation
  3. Unbiased niche labeling maps immune-excluded niche in bone metastasis

Unbiased niche labeling maps immune-excluded niche in bone metastasis

  • Cell. 2026 May 28;189(11):3287-3305.e25. doi: 10.1016/j.cell.2026.04.009.
Zhan Xu 1,  Fengshuo Liu 2,  Yunfeng Ding 1,  Tianhong Pan 3,  Yi-Hsuan Wu 2,  Yujiao Han 4,  Jun Liu 1,  Igor L Bado 5,  Weijie Zhang 1,  Ling Wu 1,  Yang Gao 6,  Xiaoxin Hao 1,  Liqun Yu 1,  Xuan Li 1,  David G Edwards 1,  Hilda L Chan 7,  Sergio Aguirre 1,  Michael Warren Dieffenbach 8,  Elina Chen 9,  Siyue Wang 10,  Yichao Shen 11,  Dane Hoffman 2,  Luis Becerra Dominguez 10,  Charlotte Helena Rivas 2,  Xiang Chen 1,  Hai Wang 12,  Yibin Kang 13,  Zbigniew Gugala 14,  Robert L Satcher 3,  Xiang H-F Zhang 15
Affiliations

Affiliations

  • 1 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 2 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Cancer and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 3 Department of Orthopedic Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Molecular Biology, Princeton University, Princeton, Princeton, NJ 08544, USA; Ludwig Institute for Cancer Research Princeton Branch, Princeton, Princeton, NJ 08544, USA.
  • 5 Icahn School of Medicine, Mount Sinai, New York, NY 10029, USA; Mount Sinai Tisch Cancer Center, New York, NY 10029, USA; Department of Oncological Sciences, Mount Sinai, New York, NY 10029, USA.
  • 6 Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
  • 7 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; The Robert and Janice McNair Foundation MD/PhD Scholars, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
  • 8 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA; Graduate Program in Development, Disease Models, and Therapeutics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 9 College of Natural Sciences, University of Texas at Austin, 110 Inner Campus Drive, Austin, TX 78706, USA.
  • 10 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Immunology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 11 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Cancer and Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
  • 12 Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
  • 13 Department of Molecular Biology, Princeton University, Princeton, Princeton, NJ 08544, USA; Ludwig Institute for Cancer Research Princeton Branch, Princeton, Princeton, NJ 08544, USA; Cancer Metabolism and Immunology Program, Rutgers Cancer Institute, New Brunswick, NJ 08903, USA.
  • 14 Department of Orthopedic Surgery and Rehabilitation, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • 15 Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 42054994 DOI: 10.1016/j.cell.2026.04.009
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

bone metastasis; estrogen receptor; estrogen signaling; fatty acid; immune exclusion; macrophage; metastatic niche; niche labeling; sortase A; tumor microenvironment.

Figures
Products