How Triple-negative Breast Cancer Becomes Resistant to Therapy

About 50% of patients diagnosed with triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer*, develop resistance to therapy. When resistance arises, tumors are more likely to recur after the initial treatment, significantly reducing the chances of survival and impacting the patient’s health-related Quality of Life (hr QoL).

Researchers at Baylor College of Medicine have discovered that TNBC can become immune to therapy in more than one way.

Their study, supported by the National Institutes of Health (NIH), the Department of Defense, the National Cancer Institute (NCI), the Breast Cancer Research Foundation, and Cancer Prevention and Research Institute of Texas, was published in the Journal of Clinical Investigation. [1] The study findings reveal two mutually exclusive mechanisms that enable TNBC to survive therapy. The findings have implications for treatment. Knowing in advance which resistance mechanism a patient’s tumor is likely to employ can guide treatment decisions to prevent or reduce resistance.

Resistance to therapy
“We have learned from the current study, together with a previous study from our lab, that there is more than one way for TNBC to become resistant to therapy,” said corresponding author, Xiang Zhang, Ph.D., professor and William T. Butler, M.D., Endowed Chair for Distinguished Faculty in molecular and cellular biology, Director of the Lester and Sue Smith Breast Center and member of the Dan L Duncan Comprehensive Cancer Center, all at Baylor. [2]

“Not every TNBC tumor is the same. Each one has a particular cellular composition of tumor cells and immune cells, such as macrophages and neutrophils. Depending on this composition, a tumor may follow a different path to develop resistance,” Zhang said.

The researchers investigated resistance pathways using patient tissue samples and mouse models. In their previous study, they had shown that in TNBCs, called epithelial-like tumors, containing macrophages and neutrophils, the latter play a major role in resistance to therapy.

But in the current study, the team discovered that neutrophils are not always the ones leading toward resistance. In other TNBCs, called mesenchymal-like tumors, which contain mostly macrophages, these immune cells play a major role in resistance development.

“We found that chemotherapy can reprogram the macrophages, transforming them from a cell that typically fights disease into one that helps tumors escape the immune response against them,” said co-first author Liqun Yu, Ph.D., a postdoctoral fellow in the Zhang lab.

“Reprogrammed macrophages engulfed and eliminated cancer cells but also produced a variety of compounds, including C1q and resolvin, that suppressed the immune attack against the tumor,” Yu added.

The researchers tested several approaches to counteract the suppressive effects of macrophages in mesenchymal-like tumors. Removing macrophages or blocking their recruitment into tumors restored the cancer’s sensitivity to treatment. Blocking compounds produced by suppressive macrophages restored immune responses against tumors, suggesting potential strategies for preventing cancer from becoming resistant to therapy.

The findings point to a potential new treatment approach.

“If we can predict the possible therapy resistance path a tumor may follow by analyzing its cellular composition before treatment, we could take actions to prevent resistance, which would increase the chances of patient survival,” Zhang concluded.

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Note:* Triple Negative Breast Cancer or TNBC is a subtype of breast cancer lacking estrogen (ER), progesterone (PR) receptors, and Human epidermal growth factor receptor 2 (HER2) protein, making it aggressive and unresponsive to hormone therapies. According to the National Cancer Institute, approximately 15% of all breast cancer patients is diagnosed with TNBC.

Reference
[1] Yu L, Rivas C, Liu F, Shen Y, Wu L, Xu Z, Ding Y, Hao X, Zhang W, Chan HL, Liu J, Wei B, Gao Y, Becerra-Dominguez L, Wu YH, Wang S, Lee TD, Li X, Chen X, Edwards DG, Zhang XH. Inflammation- and resolution-programmed myeloid circuits govern therapeutic resistance in epithelial and mesenchymal triple-negative breast cancer. J Clin Invest. 2026 Feb 17:e198815. doi: 10.1172/JCI198815. Epub ahead of print. PMID: 41701526.
[2] Yu L, Liebenberg K, Shen Y, Liu F, Xu Z, Hao X, Wu L, Zhang W, Chan HL, Wei B, Lorenzi PL, Gao Y, Bado I, Becerra-Dominguez L, Rivas CH, Aguirre S, Pingel BC, Wu YH, Ding Y, Liu J, Edwards DG, Eberlin LS, Zhang XH. Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer. Immunity. 2025 Apr 8;58(4):909-925.e7. doi: 10.1016/j.immuni.2025.03.002. Epub 2025 Mar 28. PMID: 40157359; PMCID: PMC11981829.

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