The Emergence of SFRP2 as a Target for Triple Negative Breast Cancer

Posted on 2026-03-26

Triple-negative breast cancer (TNBC) is one of the most difficult cancers to treat. Accounting for approximately 10-15% of all breast cancer cases, it lacks the hormonal and molecular markers targeted by many modern therapies [1]. As a result, treatment relies heavily on chemotherapy and radiotherapy, which are often less effective and associated with high rates of resistance. This resistance is a major driver of recurrence and metastasis in TNBC [2].

Resistance to first-line chemotherapy drugs such as doxorubicin is a persistent challenge in TNBC treatment. Once it develops, treatment options narrow significantly [3]. As a result, researchers have turned their attention to alternative targets. One area of growing interest is the tumour immune microenvironment, which in TNBC, often appears to support tumour growth rather than suppress it [4].

In this context, a study published in Breast Cancer Research, by researchers at the University of South Carolina, has identified Secreted Frizzled-Related Protein 2 (SFRP2) as an important player in this immunosuppressive environment [5].

A Target Hidden in the Tumour Microenvironment

SFRP2 is a secreted regulator of the Wnt pathway, a signalling pathway which controls cell growth and survival and is frequently dysregulated in cancer. While SFRP2 was historically thought to suppress tumour growth, more recent evidence has complicated that picture. In certain cancers, it has been linked to increased angiogenesis, cell migration and the suppression of apoptosis [5].

A key differentiator of this new study is the precise localization of SFRP2 overexpression. Using immunohistochemical staining on human TNBC tissue, the researchers demonstrated that SFRP2 is highly expressed not only by the tumour cells but also within the surrounding tumour microenvironment. Strikingly, SFRP2 was found in over 90% of tumour-associated macrophages (TAMs) and in more than 96% of tumour-infiltrating lymphocytes (TILs). This raised the possibility that SFRP2 could be contributing to the immune suppression often observed in TNBC [5].

Reprogramming the Tumour Immune Microenvironment

Macrophages are broadly classified into two distinct phenotypes: pro-inflammatory, anti-tumour M1 cells, and anti-inflammatory, pro-tumour M2 cells. In many solid tumours, the macrophages making up the immune microenvironment are skewed toward the M2 phenotype. This drives tumour growth, angiogenesis and immune evasion [6]. 

Figure 1: Macrophage polarisation. M1 macrophages are classically activated by pro-inflammatory transcription factors, which drive the expression of surface proteins such as co-stimulatory molecules and antigen presenting proteins and the secretion of pro-inflammatory cytokines. In contrast, M2 macrophages are alternatively activated through anti-inflammatory transcription factors. These drive the expression of surface proteins such as scavenger and lectin receptors and the release of immunosuppressive mediators. These distinct activation states underpin their opposing functions. The balance between these phenotypes is a key determinant of disease progression and therapeutic response.

To explore whether SFRP2 plays a role in this process, the researchers engineered a humanised monoclonal antibody designed to block its activity. Treating TAMs with this antibody significantly increased the production of IFN-γ, a cytokine linked to the M1 phenotype. This suggests that blocking SFRP2 may help shift the tumour environment towards a more anti-tumour state [5].

Promising Results in Preclinical Models

Treatment of vivo mouse models of TNBC with the antibody delivered striking results. Treatment over 11 weeks led to a 61% reduction in primary tumour volume, along with a decrease in lung metastases. In line with the previous in vitro findings, the M1/M2 macrophage ratio in lung tissue also increased, indicating a shift towards a more anti-tumour immune environment. Importantly, no obvious toxicity was observed in these models [5].

Together, these results are highly encouraging, highlighting the role of SFRP2 in shaping the tumour immune microenvironment and pointing to a promising new direction for future therapeutic strategies [5].

Targeting Chemotherapy Resistance

One of the most clinically significant findings is the ability of the antibody to remain effective despite doxorubicin resistance, a common obstacle in TNBC treatment. The researchers demonstrated that treatment with the antibody still triggers apoptosis in a doxorubicin-resistant cancer cell line. This suggests that targeting SFRP2 is a promising approach to bypass conventional treatment resistance [5].

What These Findings Mean

For patients with TNBC, the need for new treatment options remains urgent. The lack of targetable receptors has historically limited therapeutic strategies and drug resistance continues to present a major challenge [7]. 

The findings from this study are incredibly encouraging, positioning SFRP2 humanised monoclonal antibodies as a promising new targeted approach for TNBC. The antibody has now been licensed to Innova Therapeutics for further development and preparation for clinical trials [8]. This marks an important step into the drug development pipeline. 

However, as with many promising preclinical therapies, significant challenges remain. Results observed in cell lines and animal models do not always translate to human patients, where tumour complexity, immune interactions and safety considerations can significantly influence outcomes. Therefore, understanding how SFRP2-targeted therapies perform in more clinically relevant settings will be a critical next step.

Further work is also needed to better define the mechanisms underlying SFRP2 signalling and its role of shaping the tumour immune microenvironment. Given that SFRP2 has also been implicated in a range of other cancers, these findings may well have broader relevance beyond TNBC.

Figure 2: The tumour microenvironment is a complex, dynamic system in which tumour cells interact with a diverse range of stromal and immune cell populations, representing key areas of ongoing research. 1. CAFs, activated by TGF-Beta, remodel the extracellular matrix, facilitating tissue invasion.  2. EMT generates migratory tumour cells, promoting metastasis. 3. Tumour-driven angiogenesis, largely mediated via VEGF, supports tumour growth via the supply of nutrients and oxygen. 4. The tumour immune environment promotes immune evasion via macrophage polarisation and recruitment of immunosuppressive regulatory T cells. Together, these processes represent key opportunities for targeted therapeutic intervention [9].

As interest in the tumour microenvironment continues to grow, access to reliable, highly validated reagents is essential.

Abbexa offers a comprehensive range of products designed to support research into the tumour microenvironment across highly specific cancer types.

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References:

[1] Agelidis, A., Ter-Zakarian, A. and Jaloudi, M. (2025). Triple-Negative Breast Cancer on the Rise: Breakthroughs and Beyond. Breast Cancer: Targets and Therapy, [online] Volume 17, pp.523–529. doi:https://doi.org/10.2147/bctt.s516125.

[2] Agelidis, A., Ter-Zakarian, A. and Jaloudi, M. (2025). Triple-Negative Breast Cancer on the Rise: Breakthroughs and Beyond. Breast Cancer: Targets and Therapy, [online] Volume 17, pp.523–529. doi:https://doi.org/10.2147/bctt.s516125.

[3] Smoots, S.G., Schreiber, A.R., Jackson, M.M., Bagby, S.M., Dominguez, A.T.A., Dus, E.D., Binns, C.A., MacBeth, M., Whitty, P.A., Diamond, J.R. and Pitts, T.M. (2024). Overcoming doxorubicin resistance in triple-negative breast cancer using the class I-targeting HDAC inhibitor bocodepsin/OKI-179 to promote apoptosis. Breast Cancer Research, [online] 26(1). doi:https://doi.org/10.1186/s13058-024-01799-5.

[4] Racacho, K.J., Shiau, Y.-P., Villa, R., Mahri, S., Tang, M., Lin, T.-Y. and Li, Y. (2025). The tumor immune microenvironment: implications for cancer immunotherapy, treatment strategies, and monitoring approaches. Frontiers in Immunology, [online] 16. doi:https://doi.org/10.3389/fimmu.2025.1621812.

[5] Hsu, L., Siegel, J., Nasarre, P., Oberholtzer, N., Mukherjee, R., Hilliard, E., Chakraborty, P., Burge, R.A., O’Quinn, E.C., Sweatt, O., Kassir, M.F., Hobbs, G.A., Ostrowski, M., Broome, A.-M., Mehrotra, S. and Klauber-DeMore, N. (2025). Secreted frizzled-related protein 2 monoclonal antibody-mediated IFN-ϒ reprograms tumor-associated macrophages to suppress triple negative breast cancer. Breast Cancer Research : BCR, [online] 27, p.209. doi:https://doi.org/10.1186/s13058-025-02176-6.

[6] Macrophage polarization in the tumor microenvironment: Emerging roles and therapeutic potentials. (2024). Biomedicine & Pharmacotherapy, [online] 177, p.116930. doi:https://doi.org/10.1016/j.biopha.2024.116930.

[7] Xiong, N., Wu, H. and Yu, Z. (2024). Advancements and challenges in triple-negative breast cancer: a comprehensive review of therapeutic and diagnostic strategies. Frontiers in Oncology, [online] 14. doi:https://doi.org/10.3389/fonc.2024.1405491.

[8] Innova Therapeutics (2025). Innova Therapeutics to Advance Novel Cancer Treatment with Enci Therapeutics Acquisition. [online] Prnewswire.com. Available at: https://www.prnewswire.com/news-releases/innova-therapeutics-to-advance-novel-cancer-treatment-with-enci-therapeutics-acquisition-302624751.html [Accessed 18 Mar. 2026].

[9] Mondragón Morales, J., Rogel-Alvarado, R., Noverón-Figueroa, I.A. and Morales-Gutierrez, M. (2024). Immunopathological Mechanisms Observed in the Intratumoral Microenvironment and Their Relationship with Worse Prognosis in Triple-Negative Breast Cancer. Archives of Breast Cancer, [online] 11(1), pp.1–12. doi:https://doi.org/10.32768/abc.20241111-12.

Written by Eleanor Crawley