TNBC, which affects 10-15% of breast cancer patients in the United States, lacks estrogen, progesterone, and HER2 receptors, complicating treatment options due to receptor-targeting limitations. TNBC's aggressive nature, rapid growth, and resistance complicate prognosis.

Dr. Zachary Schug and colleagues devised a dual strategy that involved silencing the ACSS2 gene, which is required for TNBC metabolism, as well as increasing the immune system's response. ACSS2 regulates acetate, which is required for TNBC growth. They deactivated ACSS2 using CRISPR-Cas9 and the compound VY-3-135. Because of the excess acetate, this not only slowed TNBC growth but also triggered an immune response.

Schug’s approach successfully immunosensitized against TNBC, significantly reducing tumor growth and even eradicating cancer in some cases.

“Basically, we’ve proved that the immune system can take advantage of acetate that the tumor can’t process. It kicks the cancer while it’s down,” said Schug. “In fact, the immune system does this so well that it remembers how to attack TNBC in the future – even if that tumor’s ACSS2 gene is still active.”

Schug's research shows that inhibiting ACSS2 in combination with standard anti-breast-cancer chemotherapy improves treatment efficacy, potentially improving outcomes for TNBC patients. In human clinical trials, another group is pursuing a distinct ACSS2-inhibiting strategy.

“We knew that ACSS2 was a promising target for TNBC. Our research shows us how the immune effects of ACSS2 inhibition could eventually be used in for TNBC patients with limited treatment options,” said Schug. “More research is needed, but by combining this approach with other cancer therapies, we expect to see big improvements in treating TNBC.”