A Novel Antibody Targeting SFRP2 Protein Shows Promise for Treating Triple-Negative Breast Cancer

If breast cancer poses a significant threat to women's health, then triple-negative breast cancer (TNBC) is the most cunning and stubborn type among them. It grows rapidly, is prone to early metastasis, and more problematically, it lacks estrogen receptors, progesterone receptors, and HER2 protein-these three targets are the "sights" for many effective anti-cancer drugs. Therefore, TNBC has limited treatment options, chemotherapy remains the primary approach, and it easily develops drug resistance, often returning more aggressively after recurrence.

Recently, in a research report titled "Secreted frizzled-related protein 2 monoclonal antibody-mediated IFN-γ reprograms tumor-associated macrophages to suppress triple negative breast cancer" published in the international journal Breast Cancer Research, scientists from the Medical University of South Carolina and other institutions discovered that a novel antibody targeting the SFRP2 protein not only directly inhibits tumor growth and metastasis but also cleverly "converts" immune cells within the tumor, turning them against the cancer.

In this study, researchers focused on a molecule called secreted frizzled-related protein 2 (SFRP2). SFRP2 plays multiple villainous roles in tumors: 1) Promoting angiogenesis: supplying nutrients to the tumor, aiding its growth; 2) Anti-apoptosis: making cancer cells "immortal"; 3) Immune suppression: weakening immune cells that should attack cancer cells. Researchers used multiplex immunohistochemistry to analyze human TNBC tissues. Results showed that SFRP2 is widely present throughout the tumor microenvironment: 87% of tumor cells, 90% of tumor-associated macrophages (TAMs), and 96% of tumor-infiltrating lymphocytes (TILs) express this protein. This suggests that SFRP2 may be a key hub regulating the immune state within tumors.

Based on nearly 20 years of research on SFRP2, researchers developed a humanized monoclonal antibody (hSFRP2 mAb) and validated its multiple effects in preclinical models:

(1) "Converting" macrophages, reversing the immune situation. Macrophages are important immune cells in the tumor microenvironment and can be divided into two types: 1) M1 type: anti-cancer "warriors" that activate the immune system; 2) M2 type: "undercover agents" that suppress immunity and promote tumor growth. In the TNBC environment, macrophages mostly exhibit M2 characteristics. The study found that after treatment with the SFRP2 antibody, interferon-γ (IFN-γ) levels released by macrophages significantly increased (mRNA increased 2.35-fold, protein increased 1.9-fold), promoting their transformation into anti-cancer M1 type. In mouse models with established lung metastases, antibody treatment also increased the M1/M2 ratio in lung metastatic lesions, meaning that even when cancer has spread, the immune system can still be "retrained" to fight.

(2) Direct inhibition of tumor growth and metastasis: 1) In two TNBC mouse metastasis models, antibody treatment significantly reduced the number of lung metastatic lesions; 2) In orthotopic tumor models, the antibody inhibited MDA-MB-231 tumor growth by 61%.

(3) Overcoming chemotherapy resistance, inducing apoptosis in stubborn cancer cells: Researchers constructed TNBC cells resistant to the commonly used chemotherapy drug doxorubicin. Excitingly, the SFRP2 antibody could still effectively induce apoptosis in these drug-resistant cells, providing new insights for addressing one of the biggest challenges in clinical treatment (drug resistance).

Figure 1. SFRP2 mAb treatment reduces the number of metastases and is associated with an increase in apoptosis in tumors, as well as an increase in the M1/M2 TAM ratio and in the levels of IFN-ƴ. (Hsu L, et al., 2025)

This antibody doesn't just attack cancer cells themselves but targets SFRP2, simultaneously acting on tumor cells, macrophages, and lymphocytes, dismantling the tumor's defense and growth systems from multiple dimensions, achieving "killing multiple birds with one stone." Unlike traditional chemotherapy that "kills both good and bad," this antibody specifically accumulates in tumor tissues in vivo, with almost no accumulation in healthy organs and normal cells, potentially significantly reducing treatment side effects. It not only transforms macrophages from "accomplices" to "warriors" but also reactivates anti-cancer T cells that are typically in an "exhausted" state, offering potential to improve TNBC's poor response to immunotherapy.

Reference

Hsu L, 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, 27(1): 209.