Researchers at Cold Spring Harbor Laboratory have discovered that activating a specific fat-burning transcription factor inside immune cells can turn them into active tumor killers, offering a potential new avenue against colorectal cancer and other currently untreatable diseases.
Colorectal Cancer Death Rates in Patients Under 50 Spark New Research
Colorectal cancer has become the leading cause of cancer-related death for people under 50. Most common forms of the disease generally resist conventional treatments like chemotherapy and newer immunotherapy drugs, according to recent findings published in Nature Immunology.
To address this clinical challenge, scientists at Cold Spring Harbor Laboratory investigated whether immune cells could be metabolically reprogrammed to fight tumors more effectively. The study, led by CSHL Assistant Professor Semir Beyaz, focused on the cellular mechanisms that govern both cancer growth and immune response.
PPARD Activation Restructures the Tumor Microenvironment
Peroxisome proliferator-activated receptor delta (PPARD) normally orchestrates fat burning inside human cells. While cancer cells utilize their own PPARD to promote growth, researchers found that specifically activating PPARD on the immune side converts a pro-cancer tumor environment into an anti-cancer arena.
“It’s all about cell fitness,” Semir Beyaz explained, according to News-Medical. “What cells eat affects who they are. When immune cells burn more fat, they become more fit for fighting cancer.”
CAR T Cell Therapy Tests on Human Organoids and Mouse Models
To determine if these metabolically altered immune cells could destroy human cancer, the research team activated PPARD in synthetic immune cells known as CAR T cells. These engineered cells were then tested on organoids—miniature tumors grown directly from patient tissue samples.
The laboratory also tested the PPARD-activated CAR T cells on human cancer cells in dishes and on tumors implanted in mice. In every test, the treatment slowed or stopped tumor growth. CAR T cell therapies are already utilized in select cancer immunotherapies, lending immediate clinical relevance to these laboratory findings.
Broadening Immunotherapy to Other Tumors and Endometriosis
Although the research initially centered on colorectal cancer due to its impact on younger populations, the team validated their results across several other tumor types. These additional tests included breast cancer, ovarian cancer, and melanoma.
Semir Beyaz noted that these discoveries represent only the beginning of making cancer immunotherapy more effective. The laboratory is currently applying the same metabolic approach to endometriosis, a chronic inflammatory disease that affects one in 10 women and similarly lacks effective treatments.
Targeting Peroxisome Proliferator-Activated Receptor Delta in Human Cells
What specific transcription factor did the researchers investigate?
The researchers focused on peroxisome proliferator-activated receptor delta, or PPARD, which regulates fat burning inside human cells.
How were the laboratory tests conducted on patient tissue?
The research team tested PPARD-activated CAR T cells on organoids, which are miniature tumors grown from patient tissue samples, as well as on human cancer cells in dishes and in mouse models.
Which additional diseases are researchers targeting next with this method?
Following successful results in colorectal cancer, breast cancer, ovarian cancer, and melanoma, the lab is applying the PPARD activation approach to endometriosis.
Comparative Cellular Fitness in Disease Models
Medical researchers have long recognized overall patient fitness as a key determinant of disease outcomes. However, the Cold Spring Harbor Laboratory study bridges systemic health and cellular metabolism by demonstrating that cancer cells and immune cells operate under the same chemical and physical rules.
While disease cells utilize metabolic pathways to evade destruction, artificially boosting fat-burning capacity within immune cells provides them with the energy required to successfully outcompete tumors.
“It’s the classic fight between good and evil,” Semir Beyaz said, comparing PPARD’s dual nature to the fictional force in Star Wars. “How can good ultimately prevail? Activating PPARD in immune cells could be the way.”
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