Scientists have uncovered a powerful new antibody that disrupts a key protein helping triple-negative breast cancer survive and evade immunity.
Triple-negative breast cancer (TNBC) is considered one of the most aggressive and difficult forms of breast cancer to treat. It grows rapidly, tends to spread at an early stage, and does not have the hormone receptors that allow many other breast cancers to be treated with targeted drugs. Although some patients respond to initial therapy, the disease frequently comes back and is often more resistant to treatment the second time.
New research published in Breast Cancer Research highlights a potential way to address this challenge. Scientists at MUSC Hollings Cancer Center created an antibody designed to interfere with several processes that help TNBC cells survive, multiply, and avoid detection by the immune system. In early experiments, the antibody reduced the growth of primary tumors, limited the spread of cancer to the lungs, and restored the activity of immune cells that attack cancer. It was also effective against cancer cells that no longer responded to chemotherapy.
A new target in an immune-resistant cancer
The preclinical research centered on a protein known as secreted frizzled-related protein 2 (SFRP2). This protein plays a key role in helping cancer thrive by encouraging the formation of new blood vessels, preventing cancer cells from dying, and weakening immune cells that would normally work to destroy the tumor.
The study builds on almost twenty years of research into SFRP2 led by Nancy Klauber DeMore, M.D., a breast surgical oncologist who co leads Hollings’ Developmental Cancer Therapeutics Research Program. The project brought together a multidisciplinary team from several MUSC departments, including Surgery, Biochemistry and Molecular Biology, and Pathology and Laboratory Medicine.
“My lab first identified the role of SFRP2 in breast cancer in 2008,” Klauber-DeMore said. “Since then, we’ve discovered its mechanism of action in breast cancer growth, metastasis and immune exhaustion and developed an antibody to block SFRP2.”
For this study, the research team, which also included MUSC surgical resident Lillian Hsu, M.D., and former resident Julie Siegel, M.D., examined a humanized monoclonal antibody. This type of antibody is engineered to precisely bind to SFRP2 and limit the harmful effects it has on cancer cells.
Reprogramming the cancer’s immune environment
To confirm that SFRP2 could be a useful target for TNBC and investigate the antibody’s role in treating it, the researchers first examined human triple-negative breast tumors. They found that SFRP2 was present not only in the tumor cells themselves but also in nearby immune cells, including tumor-infiltrating lymphocytes as well as macrophages.
“This is the first time anyone has demonstrated that SFRP2 is expressed on tumor-associated macrophages,” Klauber-DeMore said. “That finding alone opens up an entirely new way of understanding and potentially manipulating the immune microenvironment.”
Macrophages can be broadly categorized into two types: M1 macrophages that activate the immune system to fight cancer and M2 macrophages that suppress immunity to help cancer grow. In TNBC, macrophages usually skew toward the M2 type. But when treated with the SFRP2 antibody, the macrophages released a surge of interferon-gamma, a key immune signal that pushed them toward the tumor-fighting M1 state. In mice whose cancer had already spread, the antibody still induced this favorable M1:M2 ratio, indicating that it could “retrain” the immune system to fight cancer even in advanced disease.
“We discovered that it pushes macrophages toward the ‘good’ M1 state – without the toxic effects you’d see if you gave interferon-gamma directly,” Hsu said. “TNBC is so hard to treat, and so many therapies come with serious toxicities, so finding a way to activate the immune system without adding new side effects is especially meaningful.”
The antibody also re-energized cancer-fighting T-cells, which often become exhausted and stop working effectively in TNBC. Once treated with the antibody, nearby T-cells became more active, suggesting that the treatment may strengthen immune responses that are often weakened in cancer and reduce the success of immunotherapy.
A highly targeted approach against cancer
In two models of advanced TNBC, mice treated with the antibody developed far fewer lung tumors than those not treated with the antibody. Lung metastases signal that cancer has spread through the bloodstream and can make outcomes far worse for patients.
Not only was the antibody effective – it was highly targeted. When the researchers tracked its movement in the body, they found that it concentrated in tumor tissue but not in healthy organs or normally growing cells. That precision contrasts with traditional chemotherapies, which kill cells more broadly and contribute to the problematic side effects that many patients experience during treatment.
Finally, the team tested whether the antibody could tackle one of the biggest hurdles in cancer treatment: resistance to chemotherapy. Doxorubicin, a standard drug used for TNBC, often works at first, but many tumors eventually stop responding. After creating cancer cells that no longer responded to doxorubicin, the researchers found that the antibody still triggered strong cell death in these hard-to-treat cells.
“That’s a very encouraging finding,” Klauber-DeMore said, “because it suggests the therapy may be effective even when standard treatments fail.”
A new therapeutic direction for treating cancer
This study revealed that SFRP2 is present at high levels in the tumor ecosystem: in both cancer cells and surrounding immune cells, including tumor-infiltrating lymphocytes and tumor-associated macrophages. That suggests the SFRP2 antibody could act on multiple fronts at once by weakening the tumor, strengthening the immune response, and bypassing treatment resistance.
Equally important, SFRP2 did not accumulate in healthy blood or immune cells, unlike many other immune-related treatments. That opens the door to adapting the antibody as a potent cancer therapy that treats the disease while minimizing unwanted side effects.
By showing that SFRP2 sits at the crossroads of tumor growth, immune suppression and treatment resistance, this study lays the foundation for a new kind of precision therapy that could work alongside or enhance existing immunotherapies for TNBC.
“Our hope,” Klauber-DeMore said, “is that this will one day offer patients a new option – one that not only treats the cancer but also re-engineers the immune system’s ability to fight it.”
While further research is needed, these early findings offer promise. The antibody has been licensed to Innova Therapeutics, a Charleston-based biotechnology company co-founded by Klauber-DeMore, which is working to raise funds for a first-in-human clinical trial. The therapy has also received Rare Pediatric Disease and Orphan Disease designations from the Food and Drug Administration (FDA) for osteosarcoma, another cancer where SFRP2 plays a major role. The FDA designations do not mean the antibody can be used in patients yet, but they provide incentives to support the drug’s development as it moves toward clinical trials.
“The preliminary data are really encouraging,” Hsu said. “I feel grateful to have been part of research that could one day help so many patients.”
Reference: “Secreted frizzled-related protein 2 monoclonal antibody-mediated IFN-ϒ reprograms tumor-associated macrophages to suppress triple negative breast cancer” by Lillian Hsu, Julie Siegel, Patrick Nasarre, Nathaniel Oberholtzer, Rupak Mukherjee, Eleanor Hilliard, Paramita Chakraborty, Rachel A. Burge, Elizabeth C. O’Quinn, Olivia Sweatt, Mohamed Faisal Kassir, G. Aaron Hobbs, Michael Ostrowski, Ann-Marie Broome, Shikhar Mehrotra and Nancy Klauber-DeMore, 5 December 2025, Breast Cancer Research.
DOI: 10.1186/s13058-025-02176-6
Funding: National Cancer Institute, National Institute of General Medical Sciences, U.S. Department of Defense, South Carolina SmartState Program
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