Scientists at the University of North Carolina Lineberger Comprehensive Cancer Center have discovered an unexpected role for a key innate immune protein, revealing how it helps regulate cholesterol levels inside cells and influences tumor growth and treatment response. The findings shed new light on how cancer cells rewire their metabolism-and point to potential new strategies for therapy.
The finding appeared November 2, 2026, in the Journal of Clinical Investigation.
The protein, called cGAS, is best known as a frontline defender against infections. When harmful DNA appears in the cell's cytoplasm, which is the material that exists between the cell membrane and the nucleus, cGAS detects the DNA and triggers an immune response. This innate immune system is the body's built-in defense system that fights off germs. But this finding shows that cGAS also works inside the nucleus, where it binds to specific regions in genome and helps control which genes are turned on or off. This nuclear role has been suspected but poorly understood until now.
"These findings reveal a completely new side of cGAS," said senior author Pengda Liu, PhD. Associate Professor of Biochemistry and Biophysics at UNC's Lineberger Comprehensive Cancer Center. "We've long thought of cGAS as an innate immune sensor, but it can also act as a regulator that controls how genes are copied from DNA to RNA and hence helps control cholesterol and cell metabolism. This dual role has major implications for cancer biology."
Using advanced techniques, the research team mapped where cGAS sits on the genome and identified the genes it regulates. In a complex biochemical chain reaction, they found that cGAS is recruited to specific regions of the genome by proteins that help control cell growth and stress responses. Once there, cGAS increases production of a protein called LGALS3, which helps control cholesterol levels and influences the behavior of cells and tumors.
This chain reaction has a major consequence: it reduces the cell's production of a molecule called acetyl‑CoA, a building block for cholesterol. With less acetyl‑CoA available, cells make less cholesterol, but when cGAS is missing the opposite occurs. Cells accumulate excess cholesterol, which alters the composition of their membranes and activates a growth‑promoting pathway. This pathway is known to increase cell size, fuel tumor growth, and make cancer cells more resistant to treatment.
To test the biological impact of this metabolic shift, the researchers studied cancer cells in the lab and implanted mouse tumor models without cGAS. Notably, tumors without cGAS grew significantly faster and showed heightened activation of a key regulatory pathway. Restoring cGAS-or simply restoring LGALS3-slowed tumor growth and reduced cholesterol buildup.
The study also found that cGAS‑deficient cancer cells were more resistant to common chemotherapy drugs such as doxorubicin, as well as cholesterol‑lowering agents. Reintroducing cGAS or LGALS3 reversed this resistance.
"We don't know whether the impact of cGAS on the key regulatory pathway could broadly affect all chemotherapy drugs or other targeted therapies solely based on cGAS's impact on cholesterol. In theory, if the tumor type depends on cholesterol for survival, this signaling may play a role in those responses," said Liu. "Also, we were able to generalize this finding to other cell types beyond cancer cells, including certain types of immune-fighting white blood cells and normal epithelial cells, and from our tests this signaling role holds true."
The discovery opens the door to new therapeutic strategies. Drugs that modulate cGAS's transcriptional activity-or target the LGALS3 pathway-could help reduce tumor growth or improve responses to existing treatments. Because cholesterol metabolism is central to many diseases, the findings may also have relevance beyond cancer.
"Our next question is to address how the regulatory role shifts, especially during different stages of tumor development, and during the development of treatment resistance. Currently we don't have any drug intervention approaches for this signaling, and we hope that follow-up studies can identify new chemical modulators that we can move forward for pre-clinical tests in different animal models," concluded Liu.
The study was funded by NIH grants R01CA244825, R01AG095618, R35GM126900, R35GM128645, R01CA271603, 1R35GM150985, T32GM067553, a Mary Kay Ash Foundation Cancer Research Grant and a North Carolina State University IBMP Fellowship.
