The research may be particularly important for colorectal cancer, which is the leading cause of cancer-related death among people under 50. For patients with difficult-to-treat forms of the disease, options are limited, especially when chemotherapy and newer immunotherapy treatments fail.

The study suggests that proteins normally associated with cancer growth may become powerful cancer-fighting forces when activated in the right cells.

Turning cancer-promoting proteins into immune system weapons

Scientists have long understood that physical fitness can affect a person’s ability to withstand disease. CSHL Assistant Professor Semir Beyaz studies a different type of fitness: the metabolic health and performance of individual cells.

“We hypothesized that the fitness determinants of cancer and immune cells might not be very different,” he said. “They’re in the same universe. They’re constrained by the same chemical and physical rules. So it’s not surprising that they end up evolving in the same way.”

At the center of the research is peroxisome proliferator-activated receptor delta, or PPARD. This protein helps regulate how cells burn fat for energy. PPARDs are transcription factors, meaning they control the activity of genes involved in important cellular processes.

To study PPARD’s effects, Beyaz and his colleagues examined mice with colorectal cancer. They found that cancer cells use PPARDs to support their own activity, while activating the same proteins in immune cells produced a dramatically different result. Instead of helping tumors grow, PPARD activation changed the surrounding environment in a way that favored the immune system’s attack.

“What’s important is cellular fitness,” Beyaz explained. “What a cell eats influences who that cell is. When immune cells burn more fat, they become better suited to fight cancer.”

Strengthening CAR T cells to fight colorectal cancer

The researchers next investigated whether boosting this fat-burning process could improve immune cells’ ability to attack human colorectal cancer.

They focused on genetically engineered immune cells known as CAR T cells. These cells are modified to recognize and attack cancer, and CAR T-cell therapy is already used to treat certain cancers.

The research team activated PPARDs in engineered CAR T cells and tested them against several experimental models of human colorectal cancer. The models included organoids, small tumor models grown from patient tissue, and human cancer cells grown in laboratory dishes and transplanted into mice.

Across these experiments, PPARD-activated CAR T cells slowed or stopped tumor growth. The results suggest that changing how immune cells process energy could make existing immunotherapy strategies more effective. However, this approach has not yet been proven in patients.

Could the approach work against other cancers?

Colorectal cancer was the initial focus because of its increasing prevalence among younger people. However, the researchers also found promising results in breast cancer, ovarian cancer, and melanoma, a serious form of skin cancer.

These findings raise the possibility that improving immune-cell fitness could become a broader strategy for treating tumors that are difficult to control with current therapies.

Beyaz believes the discovery is only the “tip of the iceberg” when it comes to finding new ways to enhance cancer immunotherapy.

Potential applications beyond cancer

Strengthening immune-cell fitness could potentially help in other conditions in which the immune system is unable to eliminate diseased cells.

“Strengthening immune cell fitness may also help in other conditions where the immune system is unable to eliminate diseased cells,” Beyaz said.

His lab is currently studying whether the same approach could help treat endometriosis, a chronic inflammatory disease that affects about one in 10 women. Like colorectal cancer, endometriosis remains a major medical challenge, and existing treatments often fail to provide lasting symptom relief.

Why the same protein can help or harm

Beyaz compares PPARD’s contradictory roles to the power of the Star Wars universe. Depending on how it is used, the same fundamental force can produce very different results.

In cancer cells, PPARDs may support disease progression, much like Darth Vader serving the Emperor. When activated in immune cells, however, they can play the opposite role and help destroy disease, similar to Anakin Skywalker’s return to the light.

“This is a classic battle between good and evil,” Beyaz said. “How can we finally make sure that good prevails? Activating PPARDs in immune cells may be the way to do that.”