The findings, published in Nature Immunology, could be especially important for colorectal cancer, which has become the leading cause of cancer-related death among people under 50. Many patients with difficult-to-treat forms of the disease have limited options, particularly when chemotherapy and newer immunotherapy treatments fail. The research suggests that a protein normally associated with cancer growth could instead become a powerful cancer-fighting "force" when activated in the right cells.

Turning a Cancer-Promoting Protein Into an Immune System Weapon

Scientists have long understood that a patient's physical fitness can influence their ability to withstand illness. But CSHL Assistant Professor Semir Beyaz is exploring a different kind of fitness: the metabolic health and performance of individual cells.

"We hypothesized that the fitness determinants of cancer and our immune cells may not be so different," he said. "They're in the same universe. They're constrained by the same chemical and physical rules. So, it's not surprising they'd end up evolving the same way."

At the center of the research is peroxisome proliferator-activated receptor delta (PPARD), a protein that helps regulate how cells burn fat for energy. PPARD is a transcription factor, meaning it controls the activity of genes involved in important cellular processes.

To understand its effects, Beyaz and his colleagues began by studying mice with colorectal cancer. They found that although cancer cells use PPARD to support their own activity, activating the same protein in immune cells had a dramatically different effect. Instead of helping tumors thrive, it shifted the surrounding environment toward one that favored the immune system's attack on cancer.

"It's all about cell fitness," Beyaz explains. "What cells eat affects who they are. When immune cells burn more fat, they become more fit for fighting cancer."

Supercharging Cancer-Fighting CAR T Cells

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

They turned to engineered immune cells known as CAR T cells. These cells are modified to recognize and attack cancer, and CAR T cell therapies are already used to treat certain cancers.

The team activated PPARD in the engineered cells and tested them against several experimental models of human colorectal cancer. These included organoids, which are miniature tumor models grown from patient tissue, as well as human cancer cells cultured in laboratory dishes and implanted into mice.

Across these experiments, the 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, although the approach has not yet been proven in patients.

A Potential Strategy Against Multiple Types of Cancer

Colorectal cancer was the researchers' initial focus because of its growing toll on younger adults. However, the team also confirmed promising results in other cancers, including 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 discoveries represent only the "tip of the iceberg" when it comes to finding new ways to strengthen cancer immunotherapy.

The potential applications may also extend beyond cancer.

"Boosting immune cell fitness may also help with other conditions where the immune system fails to clear diseased cells," Beyaz says.

His laboratory is now investigating whether the same approach could help treat endometriosis, a chronic inflammatory condition affecting approximately one in 10 women. Like difficult-to-treat colorectal cancer, endometriosis remains a major medical challenge, with existing treatments often unable to provide lasting relief.

The Surprising Good and Evil Sides of a Cancer Protein

Beyaz compares PPARD's opposing roles to "the force" in Star Wars. Depending on how it is used, the same underlying power can produce very different outcomes.

In cancer cells, PPARD can support disease progression, much like Darth Vader serving the Emperor. But when activated in immune cells, it can take on the opposite role, resembling Anakin Skywalker's return to the light and helping destroy the disease instead.

"It's the classic fight between good and evil," Beyaz says. "How can good ultimately prevail? Activating PPARD in immune cells could be the way."