New Method Sheds Light on Cellular Environments That Promote Metastatic Cancer Growth

Understanding how metastatic cancer thrives in distant organs has long been a key challenge in oncology. Now, scientists at Baylor College of Medicine and collaborating institutions have developed a novel technique, Sortase A–Based Microenvironment Niche Tagging (SAMENT), to precisely map the cellular composition of the microenvironments—or “niches”—that support metastatic tumor growth, but also uncovered an unexpected driver of immune suppression in bone metastasis. Their findings, published in Cell, offer new insights into the biology of metastasis and identify a potential therapeutic target across multiple cancer types. [1]

Decoding the Metastatic Niche
Metastasis, the spread of cancer cells from the primary tumor to distant organs, is the leading cause of death in patients with solid tumors. The ability of cancer cells to colonize and grow in new environments depends not only on the cancer cells themselves but also on their interactions with surrounding normal cells. These interactions can profoundly influence tumor behavior, therapeutic responses, and patient outcomes.

“As tumors progress, cancer cells leave the original site and spread or metastasize to other organs where they seed new tumors. Our lab seeks to understand which cellular and molecular features in distant tissues allow metastases to take hold and grow. Identifying these features could inform strategies to prevent or disrupt metastatic disease,”  explained Xiang Zhang, Ph.D., senior author and director of the Lester and Sue Smith Breast Center at Baylor

Introducing SAMENT: Labeling the Tumor Microenvironment
During metastasis, cancer cells constantly interact with normal cells in the body, and these interactions affect cell behavior, fate, and even response to therapies.

The team developed SAMENT, a method that selectively labels normal cells in direct contact with metastatic cancer cells in living tissue. This innovative approach enables researchers to pinpoint and analyze the specific populations of cells that interact with and support metastatic cancer cells, even when these interactions are fleeting.

“Our method allowed us to identify specific cells encountered by cancer cells during metastasis,” said co-first author Fengshuo Liu, a graduate student in the Cancer and Cell Biology Program working in the Zhang lab.

Applying SAMENT across various cancer models and organs—including bone, lung, liver, and brain—the researchers discovered that pro-metastatic niches share two common features: an abundance of macrophages (a type of immune cell) and a marked scarcity of T-cells, which are usually responsible for attacking tumor cells.

A Unique Immune Barrier in Bone Metastasis
While this macrophage-rich, T-cell–depleted signature was observed in every organ studied, bone metastases displayed a unique twist. The macrophages surrounding metastatic cancer cells in bone were found to express estrogen receptor alpha (ERα), a protein best known for its role in hormone-responsive breast cancer. This ERα activity in macrophages was not observed in normal bone or in primary tumors elsewhere, and was identified in bone metastases from patients with breast, lung, and kidney cancers—including in men.

Further experiments revealed that cancer cells ‘educate’ macrophages to become immunosuppressive bodyguards by delivering fatty acids, which activate ERα signaling in these immune cells. Once activated, ERα+ macrophages act as a physical and chemical barrier, preventing T-cells from reaching and attacking tumor cells in the bone.

Therapeutic Implications: Disabling the Shield
To test the importance of this immune barrier, the researchers genetically deleted the ERα gene in macrophages in mouse models. This intervention allowed T-cells to infiltrate bone metastases, sharply reducing tumor colonization and slowing tumor growth. Remarkably, normal bone health was unaffected.

Additionally, treating mice with fulvestrant (Faslodex®; AstraZeneca [original developer])—a US Food and Drug Administration (FDA) approved estrogen receptor degrader—similarly enabled T-cell infiltration and tumor cell killing in bone metastases. These results suggest that blocking ERα in macrophages could become a powerful strategy to enhance immune attack on bone metastases, regardless of cancer type or patient sex.

A New Frontier in Metastasis Research
SAMENT represents an important advance in profiling the complex and dynamic tumor microenvironment. By unbiasedly tagging and analyzing niche cells that interact with metastatic seeds, the method revealed a previously unrecognized, ERα-driven immunosuppressive niche in bone metastasis.

“Our findings provide a rationale for clinical trials testing estrogen-blocking therapies in combination with immunotherapies for patients with bone metastases from different cancers,” Zhang said.

“Targeting the ERα+ macrophage barrier could open new avenues to treat metastasis more effectively,” he concluded.
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Highlights of Prescription Information
Fulvestrant (Faslodex®; AstraZeneca [original developer])[Prescribing Information]

References:
[1] Zhang X, Liu F, Ding Y, Pan T, Wu YH, Han Y, Liu J, Bado IL, Zhang W, Wu L, Gao Y, Hao X, Yu L, Li X, Edwards DG, Chan HL, Aguirre S, Dieffenbach MW, Chen E, Wang S, Shen Y, Hoffman D, Dominguez LB, Rivas CH, Chen X, Wang H, Kang Y, Gugala Z, Satcher RL, Zhang XHF. Unbiased niche labeling maps immune-excluded niche in bone metastasis. Cell https://doi.org/10.1016/j.cell.2026.04.009.

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