A new experimental antibody developed at the Medical University of South Carolina Hollings Cancer Center may finally turn the tide against triple-negative breast cancer, one of the most aggressive and treatment-resistant forms of the disease. Published in Breast Cancer Research, the groundbreaking study reveals that the therapy not only slows primary tumor growth and reduces metastatic spread but also reprograms the immune system to recognize and attack cancer cells, even those that have become resistant to chemotherapy.
Rewiring the Immune Landscape Around Tumors
What makes this discovery particularly remarkable is the antibody’s multi-pronged approach to fighting cancer. Unlike traditional treatments that target a single pathway, this therapy attacks the disease on multiple fronts simultaneously. The researchers identified secreted frizzled-related protein 2 (SFRP2) as a central orchestrator enabling tumors to thrive, evade immune detection, and resist treatment.
When the research team analyzed human triple-negative breast cancer samples, they made a surprising discovery: SFRP2 appeared not only within cancer cells but throughout the surrounding tumor microenvironment – in immune cells called tumor-infiltrating lymphocytes, in tumor-associated macrophages, and even in B-cells. This widespread presence suggested that targeting SFRP2 could disrupt multiple cancer-enabling processes at once.
Dr. Nancy Klauber-DeMore, a breast surgical oncologist who co-leads the Developmental Cancer Therapeutics Research Program at Hollings, emphasized the significance of finding SFRP2 on tumor-associated macrophages for the first time. This discovery alone opens entirely new possibilities for understanding and manipulating the immune microenvironment surrounding tumors.
Macrophages generally fall into two categories with opposing functions. M1 macrophages activate immune responses that fight cancer, while M2 macrophages suppress immunity and actively support tumor growth. In triple-negative breast cancer, the balance typically shifts heavily toward immunosuppressive M2 macrophages, essentially creating a protective shield around the tumor that prevents the immune system from attacking.
The experimental antibody dramatically altered this balance. After treatment, macrophages released massive amounts of interferon-gamma, a crucial immune signaling molecule that pushed them back toward the cancer-fighting M1 state. Most importantly, this immune reprogramming occurred without the toxic side effects associated with directly administering interferon-gamma, a significant advantage since triple-negative breast cancer treatments already come with substantial toxicity concerns.
Understanding Triple-Negative Breast Cancer’s Unique Challenges
Triple-negative breast cancer represents approximately 10-15 percent of all breast cancers but accounts for a disproportionate share of breast cancer deaths. The designation “triple-negative” refers to the absence of three receptors that define other breast cancer subtypes: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2). This lack of targetable receptors has historically limited treatment options to cytotoxic chemotherapy.
The disease strikes younger women more frequently than other breast cancer types and shows higher rates among African American and Hispanic women. It grows rapidly, spreads early to distant organs, and frequently returns after initial treatment, often more aggressively the second time. According to the National Cancer Institute, five-year survival rates for metastatic triple-negative breast cancer remain discouragingly low at approximately 12 percent.
Recent advances in immunotherapy have provided new hope. The FDA approval of pembrolizumab (Keytruda) combined with chemotherapy marked a significant breakthrough for patients with PD-L1-positive tumors. However, this combination benefits only about 40 percent of triple-negative breast cancer patients, those whose tumors express high levels of PD-L1. The remaining majority still lack effective targeted therapies beyond chemotherapy.
Twenty Years of Research Culminates in Clinical Promise
The MUSC team’s findings build on nearly two decades of research. Dr. Klauber-DeMore first identified SFRP2’s role in breast cancer in 2008. Since then, her laboratory has systematically unraveled how this protein promotes tumor growth, facilitates metastasis, and contributes to immune exhaustion, the state where immune cells become functionally inactive despite being present in the tumor microenvironment.
The current study, co-led by surgical resident Dr. Lillian Hsu and former resident Dr. Julie Siegel, tested a humanized monoclonal antibody engineered to precisely bind SFRP2 and neutralize its cancer-promoting effects. Humanized antibodies are designed to minimize immune reactions while maintaining therapeutic potency, making them suitable for eventual human clinical trials.
In preclinical testing using two different advanced triple-negative breast cancer models, mice treated with the antibody developed significantly fewer lung metastases compared to untreated controls. Lung metastases indicate cancer has entered the bloodstream and spread systemically, a development associated with dramatically worse patient outcomes and limited treatment options.
The antibody’s targeting precision proved remarkably specific. When researchers tracked where it traveled within the body, they found substantial accumulation in tumor tissue but minimal presence in healthy organs or normal cells. This selective distribution differs fundamentally from conventional chemotherapy, which affects rapidly dividing cells throughout the body and causes widespread side effects including hair loss, nausea, immune suppression, and organ damage.
Breaking Through Chemotherapy Resistance
Perhaps most encouraging, the antibody demonstrated effectiveness against one of oncology’s greatest challenges: acquired chemotherapy resistance. The researchers created cancer cell lines that no longer responded to doxorubicin, a cornerstone chemotherapy drug for triple-negative breast cancer. Despite this resistance, the SFRP2 antibody still caused substantial cancer cell death.
This finding carries profound implications for clinical practice. Many triple-negative breast cancer patients initially respond well to chemotherapy but experience recurrence with tumors that have adapted to resist the same drugs. These patients face severely limited treatment options and poor prognoses. A therapy that bypasses chemotherapy resistance mechanisms could potentially help this particularly vulnerable population.
The antibody also restored activity in T-cells, another critical component of immune defense. In triple-negative breast cancer, these cells often become exhausted and stop functioning properly, a phenomenon scientists call T-cell exhaustion. After antibody treatment, T-cells regained their cancer-fighting capabilities, suggesting the therapy could strengthen immune responses that immunotherapy drugs like pembrolizumab depend upon to work effectively.
From Laboratory Discovery to Clinical Reality
According to research published in Breast Cancer Research, the antibody’s effects persisted even in mice with advanced disease and existing metastases. This demonstrates potential utility not just for early-stage disease but for patients whose cancer has already spread, currently the most challenging clinical scenario.
The research identified SFRP2 as abundant throughout the tumor ecosystem, appearing in malignant cells, surrounding immune cells including tumor-infiltrating lymphocytes, and tumor-associated macrophages. This widespread presence suggests that targeting SFRP2 could simultaneously weaken tumors, boost immune activity, and potentially bypass treatment resistance through multiple independent mechanisms.
Importantly, SFRP2 did not accumulate in healthy blood cells or normal immune cells from non-cancerous tissues. This selectivity distinguishes the antibody from many immunotherapy approaches and supports its potential as a treatment that limits collateral damage while maintaining effectiveness against cancer.
The therapy has been licensed to Innova Therapeutics, a Charleston-based biotechnology company co-founded by Dr. Klauber-DeMore, which is working to secure funding for first-in-human clinical trials. The antibody has also received Rare Pediatric Disease and Orphan Disease designations from the Food and Drug Administration for osteosarcoma, another cancer where SFRP2 plays a central role. While these designations don’t permit immediate patient use, they provide regulatory incentives and development support that could accelerate the path to clinical availability.
A New Paradigm for Combination Therapy
The MUSC findings align with broader trends in cancer treatment emphasizing combination approaches. Rather than replacing existing therapies, the SFRP2 antibody could potentially enhance their effectiveness. By converting immunosuppressive macrophages into cancer-fighting allies and reactivating exhausted T-cells, the antibody might create conditions where checkpoint inhibitors like pembrolizumab work more effectively.
This concept of immune priming (using one therapy to prepare the tumor microenvironment for another) represents an active area of investigation across multiple cancer types. According to recent research in Cancers, combining immunotherapies with therapies that modulate the tumor microenvironment shows particular promise for overcoming the limitations of single-agent immunotherapy.
The precision with which the antibody targets tumor tissue while sparing healthy organs suggests it could be combined with chemotherapy without compounding toxicity. If the antibody helps overcome chemotherapy resistance while causing minimal side effects of its own, it might allow dose reductions of toxic chemotherapy drugs while maintaining or improving treatment effectiveness.
Dr. Klauber-DeMore expressed the team’s ultimate goal: offering patients a treatment option that not only attacks cancer but fundamentally re-engineers the immune system’s capacity to fight it. By identifying SFRP2 as a nexus connecting tumor growth, immune suppression, and drug resistance, the research points toward a new class of precision therapies that could complement or amplify existing immunotherapies for triple-negative breast cancer.
While additional studies including clinical trials will be necessary to confirm these preliminary findings in human patients, the early results provide genuine cause for optimism. Dr. Hsu, reflecting on the research journey, expressed gratitude for contributing to work that could eventually help the many patients struggling with this aggressive disease.
As the medical community continues searching for more effective treatments for triple-negative breast cancer, this multi-targeted approach represents a significant step forward, offering hope that one of oncology’s most challenging diseases may finally yield to smarter, more sophisticated therapeutic strategies.
Study Citation: Lillian Hsu, Julie Siegel, et al., “Secreted frizzled-related protein 2 monoclonal antibody-mediated IFN-ϒ reprograms tumor-associated macrophages to suppress triple negative breast cancer,” Breast Cancer Research (2025). DOI: 10.1186/s13058-025-02176-6
