Triple-negative breast cancer is one of the most aggressive and treatment-resistant cancers. It grows quickly, spreads early, and lacks hormone receptors that make it treatable with targeted therapies. Even when patients initially respond to treatment, the cancer often returns and is more resistant.
A study in Breast Cancer Researchpoints to a promising strategy to overcome this resistance. Researchers at MUSC Hollings Cancer Center developed an antibody that blocks several survival pathways that TNBC cells rely on. In early testing, the antibody suppressed tumor growth, reduced lung metastases, reenergized immune cells, and killed cancer cells that had stopped responding to chemotherapy.
Targeting an immune-resistant cancer
The study focused on secreted frizzled-related protein 2 (SFRP2), a protein that fuels tumor growth by promoting new blood vessels, blocking cell death and weakening immune cells. Breast surgical oncologist Nancy Klauber-DeMore, MD, has spent nearly two decades researching SFRP2.
“My lab first identified SFRP2’s role in breast cancer in 2008,” Klauber-DeMore said. “Since then, we’ve discovered its mechanisms of action and developed an antibody to block SFRP2.”
In this study, Klauber-DeMore and a multidisciplinary team of MUSC researchers tested a humanized monoclonal antibody designed to attach to SFRP2 and inhibit its cancer-causing effects.
Reprogramming the immune environment
To confirm that SFRP2 is a strong therapeutic target, the researchers first examined human TNBC tumors. They found that SFRP2 appears not only in cancer cells but also in nearby immune cells, including tumor-infiltrating lymphocytes and tumor-associated macrophages.
“This is the first time anyone has demonstrated that SFRP2 is expressed on macrophages,” Klauber-DeMore said. “That finding opens up an entirely new way of understanding and potentially manipulating the immune microenvironment.”
Macrophages fall into two broad categories: M1 macrophages activate the immune system, while M2 macrophages suppress immunity. In TNBC, macrophages skew heavily toward the M2 type. But treatment with the SFRP2 antibody released a surge of interferon-gamma, which pushed macrophages toward the cancer-fighting M1 state. This shift occurred even in mice with metastatic disease, indicating the antibody could “retrain” the immune system to fight advanced cancer.
“It pushes macrophages toward the M1 state—without the toxic effects of giving interferon-gamma directly,” said co-first author Lillian Hsu, MD “TNBC is so hard to treat, and so many therapies come with serious toxicities, so activating the immune system without adding new side effects is incredibly meaningful.”
The antibody also re-energized cancer-fighting T-cells, which often lose function in TNBC. Once treated with the antibody, nearby T-cells became more active, suggesting the therapy strengthens immune responses that often weaken in cancer and hinder immunotherapy.
Treating cancer with precision
In models of advanced TNBC, mice treated with the antibody developed far fewer lung metastases than untreated mice. Lung metastases signal that cancer has spread and worsen patient outcomes. Notably, the antibody accumulated in tumor tissue and not in healthy organs or normally growing cells.
The antibody also tackled one of cancer therapy’s biggest hurdles: chemotherapy resistance. Doxorubicin, a standard TNBC drug, often stops working as tumors adapt. When the researchers tested the antibody in a doxorubicin-resistant cell line, it 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 treatment direction
This study showed that SFRP2 sits at the intersection of tumor growth, immune suppression and treatment resistance. By targeting SFRP2 across cancer and immune cells, the antibody could weaken tumors, strengthen immune responses and overcome treatment resistance, laying the foundation for a new type of precision therapy.
Equally important, SFRP2 did not accumulate in healthy blood or immune cells, raising the potential for a highly targeted therapy with fewer side effects than many current treatments. While more research is needed, these findings offer early translational promise. The antibody has been licensed to Innova Therapeutics, a Charleston biotechnology company co-founded by Klauber-DeMore, which is working to advance it toward a first-in-human clinical trial.
Our hope. 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.
Nancy Klauber-DeMore
“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.”
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. Secreted Frizzled-Related Protein 2 Monoclonal Antibody-Mediated IFN-ϒ Reprograms Tumor-Associated Macrophages to Suppress Triple Negative Breast Cancer. Breast Cancer Research. [5 December 2025]. doi: 10.1186/s13058-025-02176-6.
Funding from the South Carolina SmartState Program (W81XWH-18-1-0007), National Cancer Institute (P30CA138313), National Institute of General Medical Sciences (P20GM130457), Department of Defense Breakthrough Level II Award and Hollings Cancer Center Abney Fellowship supported this research.
