Nearly half of patients with triple-negative breast cancer (TNBC) eventually develop resistance to therapy, a major factor that increases the likelihood of tumor recurrence and lowers survival rates. Researchers at Baylor College of Medicine have now uncovered that TNBC can evade treatment through more than one mechanism, findings that could guide personalized strategies to prevent resistance.
Published in the Journal of Clinical Investigation, the study reveals two distinct and mutually exclusive pathways by which TNBC tumors survive therapy. Understanding which resistance mechanism a patient’s tumor is likely to adopt could inform treatment decisions and improve outcomes.
“From this study, alongside our previous work, we have learned that there isn’t a single route for TNBC to develop therapy resistance,” said Dr. Xiang Zhang, corresponding author, professor, and William T. Butler, M.D., Endowed Chair for Distinguished Faculty in molecular and cellular biology, as well as Director of the Lester and Sue Smith Breast Center at Baylor. “Each TNBC tumor has a unique composition of cancer cells and immune cells, such as macrophages and neutrophils. This cellular makeup influences the specific path a tumor may take to resist therapy.”
Using patient tissue samples and mouse models, the team examined the immune cell interactions within tumors. Their earlier research identified that in epithelial-like TNBC tumors, which contain both macrophages and neutrophils, neutrophils play a critical role in developing resistance.
However, the current study shows that neutrophils are not always the primary drivers of resistance. In mesenchymal-like TNBC tumors, which are rich in macrophages, these immune cells become central to therapy evasion.
“Chemotherapy can reprogram macrophages, transforming them from disease-fighting cells into ones that help tumors evade the immune system,” explained co-first author Dr. Liqun Yu, postdoctoral fellow in the Zhang lab. “These reprogrammed macrophages engulf cancer cells but also release compounds like C1q and resolvin that suppress the body’s immune attack against the tumor.”
The researchers explored strategies to counteract these suppressive macrophages. Removing macrophages, blocking their recruitment, or inhibiting the compounds they produce successfully restored tumor sensitivity to treatment, highlighting potential approaches to prevent TNBC from becoming therapy-resistant.
“Our findings suggest that by analyzing a tumor’s cellular composition before treatment, we could predict the resistance pathway it might follow,” Zhang said. “This knowledge would allow clinicians to intervene proactively, improving the likelihood of patient survival.”
