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Breaking Down Lipid Storage in Triple Negative Breast Cancer Cells May Help Overcome Treatment Resistance
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Key Takeaways
- Targeting lipid buildup in TNBC cells can restore treatment sensitivity and enhance immune response, offering a new strategy against therapy resistance.
- Fatty acids not only serve as an energy source but also contribute to immunosuppressive signaling, complicating treatment responses.
Fatty acid metabolism plays a critical role in treatment responses.
Researchers may have found a way to reverse therapy resistance in triple-negative breast cancer (TNBC), according to findings published in Immunity. The study suggests that breaking down fat storage in cancer cells can restore treatment sensitivity and enhance immune response. These findings could help guide strategies to overcome resistance to anti–programmed cell death protein-1 (anti–PD-1) therapies and chemotherapy by targeting lipid buildup within tumors.1
Biochemical illustration of fatty acid synthesis | Image Credit: © VRAYVENUS - stock.adobe.com
“The prevailing perspective in our field has focused on the role of fatty acid metabolism in regulating the immune response and therapeutic response. We found in this study that not only can fatty acids serve as an energy source, but they also are precursors of immunosuppressive signals the cancer cells can use to fight against our immune system,” said corresponding author Xiang Zhang, MD, director of the Lester and Sue Smith Breast Center and professor of molecular and cellular biology at Baylor.2
BC is the most common malignancy among women in the United States and is the second leading cause of cancer-related mortality. TNBC is an aggressive subtype that accounts for approximately 15% of all instances of BC in the United States with limited therapeutic options due to a lack of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2) in tumor cells. The absence of these receptors results in poor or no response to standard chemotherapies, hormone therapies, endocrine therapies, or immunotherapies.3,4
Understanding the factors driving resistance is crucial to ensure optimal treatment responses and, thereby, better patient outcomes. In a mouse model, the researchers observed metabolic phenomena underlying metabolic factors regulating immune response and therapeutic response. They used single-cell RNA sequencing to uncover a subset of fat-containing neutrophils resembling adjacent tumor cells.1
When mice were fed less omega-6 fats (which are used to make arachidonic acid [AA]) or when AA production was blocked, the immune system responded better, and previously resistant tumors became sensitive again to anti-PD-1 drugs and chemotherapy. In human patients, higher AA activity was linked to more neutrophils in the tumor.1
“We found the tumor cells give the lipid droplets to surrounding neutrophils. This shifted the function of the neutrophils from antitumor to tumor promotion,” said first author Liqun Yu, MD, postdoctoral fellow in the Zhang lab at Baylor.2
Overall, the study shows that fat buildup in TNBC cells weakens the immune system and makes the cancer harder to treat. The findings suggest that breaking down fat storage in cancer cells can help overcome treatment resistance and boost the immune response, offering another approach to overcoming poor treatment responses in patients with TNBC.
“We can advise patients to consume a diet low in omega-6 fatty acids, which is not significantly different from the general advice to lower red meat, fat, and sodium intake,” said Zhang and William T. Butler, MD, Endowed Chair for Distinguished Faculty and co-leader of the Breast Cancer Program at the Dan L Duncan Comprehensive Cancer Center at Baylor. “We also are exploring therapeutic options to block fatty acid accumulation and immunosuppressive signals between the cancer cells and the neutrophils.”2
