WINSTON-SALEM, N.C., Sept.,18, 2026 — Researchers at Wake Forest University School of Medicine have identified a protein that may help an aggressive form of breast cancer spread to the brain and escape the body's immune defenses.
The study found that SIRPα, a protein best known for regulating immune cells, also appears to act inside triple-negative breast cancer cells. In preclinical models, higher levels of the protein made the cancer cells more likely to spread while weakening the brain's immune response against them.
The findings were recently published in Neuro-Oncology by Tsai YT et al.
Triple-negative breast cancer, or TNBC, is an aggressive form of breast cancer that lacks three common markers used to guide treatment. It has a greater tendency than many other breast cancers to spread to the brain, where treatment options remain limited and outcomes are often poor.
The new findings offer a possible explanation for how TNBC cells establish tumors in the brain and identify SIRPα as a potential focus for future treatment research. The results are preclinical, however, and additional studies are needed before the approach can be evaluated in patients.
"The biology of brain metastasis is incredibly complex, and we urgently need better ways to prevent and treat it," said David R. Soto-Pantoja, Ph.D. , corresponding author and associate professor of cancer biology at Wake Forest University School of Medicine. "Our findings suggest that SIRPα helps make tumor cells more aggressive while also changing the brain environment in ways that help those cells survive."
A protein with a surprising role
By examining human breast cancer data and tumor samples, researchers found higher levels of SIRPα in TNBC cells, particularly in tumors that had spread to the brain. Higher SIRPα levels were also associated with poorer outcomes among patients with TNBC.
Laboratory experiments suggested that SIRPα changes the behavior of mitochondria, the structures that produce energy within cells. In cancer cells with high levels of SIRPα, the mitochondria broke into smaller pieces through a process called mitochondrial fission. This change made the cancer cells more mobile and more likely to spread in the study models.
Helping cancer spread — and hide
The researchers also found that SIRPα increased production of fibronectin, a protein that helps provide structure and support around cells. Fibronectin appeared to weaken the response of microglia, immune cells that help protect the brain. With repeated exposure to fibronectin, the microglia became less able to trigger inflammation and attack the cancer cells.
"One of the most intriguing findings was that the tumor cells appeared to weaken the response of the brain's immune cells," Soto-Pantoja said. "This creates a more favorable environment for cancer cells to grow and survive, and SIRPα appears to play an important role in that process."
Putting the theory to the test
The researchers analyzed human breast cancer data and patient tumor samples and conducted experiments involving breast cancer cells, immune cells and mitochondria. They also used preclinical models designed to reproduce the spread of breast cancer to the brain.
Across several models, reducing or inhibiting SIRPα slowed tumor growth, decreased the amount of cancer found in the brain and delayed the development of brain metastases. It also reversed some of the changes that helped cancer cells evade the brain's immune response.
What this could mean for treatment
Most experimental treatments involving the CD47-SIRPα pathway have focused on its role in immune cells. These findings suggest that targeting SIRPα could potentially have an additional effect by interfering directly with processes inside cancer cells that help them spread.
The study also connects several biological processes involved in brain metastasis, including changes in how cancer cells produce energy, their surrounding structural environment and the brain's immune response. Understanding how these processes work together could inform future treatment research for patients with TNBC that has spread, or is at high risk of spreading, to the brain.
The next questions researchers hope to answer
The investigators plan to continue studying how SIRPα functions in cancer cells and whether it can be safely targeted. Future studies will also explore whether blocking SIRPα could enhance existing immunotherapies or other treatments for TNBC brain metastases.
The NCI-designated Comprehensive Cancer Center at Atrium Health Wake Forest Baptist, in partnership with Wake Forest University School of Medicine, the academic core of Advocate Health, advances cancer care through leadership in more than 1,000 clinical trials nationwide.
This research was supported by the American Society for Radiation Oncology-Breast Cancer Research Foundation Career Development Award to End Breast Cancer; National Cancer Institute grant R21CA249349; the Lewis-Michael Miracle Fund; an Atrium Health Wake Forest Baptist Comprehensive Cancer Center Brain Tumor Center of Excellence Pilot Award; American Cancer Society Post-Baccalaureate Training Program grant 11000003871; and the National Cancer Institute Intramural Research Program grant ZIA BC 011877.
About Wake Forest University School of Medicine
Wake Forest University School of Medicine is the academic core of Charlotte, North Carolina-based Advocate Health and a recognized leader in experiential medical education and groundbreaking research. It directs the education of nearly 1,900 students and fellows, including physicians, basic scientists and allied clinical professionals. The school of medicine also strategically investigates opportunities that will expand basic and clinical research, resulting in nationally and internationally recognized excellence in biomedical research. The school has two campuses, each co-located with leading-edge innovation districts, The Pearl , in Charlotte, and Innovation Quarter , in Winston-Salem, North Carolina. These affiliated life-sciences innovation districts focus on advancing health care through new medical technologies and biomedical discovery.
About Advocate Health
Headquartered in Charlotte, North Carolina, Advocate Health is the third-largest nonprofit, integrated health system in the United States. A preeminent academic health system at the forefront of clinical excellence, innovation and research, it delivers care under the names Advocate Health Care in Illinois; Atrium Health in the Carolinas, Georgia and Alabama; and Aurora Health Care in Wisconsin and Michigan, and Wake Forest University School of Medicine
