Cancer-promoting protein also helps engineered immune cells fight tumors in lab tests

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by Jen A. Miller, Cold Spring Harbor Laboratory

edited by Sadie Harley, reviewed by Robert Egan

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PPARD activation in the immune system increases the presence of tumor-infiltrating immune cells (green) in colorectal cancer, thereby suppressing tumor cells (blue and red) and slowing the cancer's growth. Credit: Beyaz lab/CSHL

Colorectal cancer has become the leading cause of cancer-related death for people under 50. Its most common forms generally aren't treatable, either through conventional means like chemotherapy or newer immunotherapy drugs.

New research at Cold Spring Harbor Laboratory (CSHL), published in Nature Immunology, could someday give people living with colorectal cancer—and other currently untreatable diseases—a fighting chance. The findings suggest a transcription factor that usually promotes cancer growth can be turned into a cancer-fighting "force" inside the immune system.

Turning fat burning against cancer

In the battle against disease, doctors have long recognized fitness as one of the strongest determinants of patient outcomes. But for CSHL assistant professor Semir Beyaz, fitness means more than physique.

"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."

Peroxisome proliferator-activated receptor delta (PPARD) helps orchestrate fat burning inside human cells. To investigate this transcription factor's role in health and disease, Beyaz's lab first focused on a mouse model of colorectal cancer. The team found that while cancer cells have their own PPARD, activating PPARD on the immune side turns a pro-cancer tumor environment into an anticancer arena.

"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."

Though used to treat blood cancers, CAR T-cell therapy has had limited success against solid tumors. Activating PPARD in the immune cells could change that. Here, CAR T cells with (right) and without (left) PPARD activation are tested on colorectal cancer organoids. CAR T cells are shown in green, and organoids in red. How effective the different CAR T-cell groups are at killing off the organoids is measured in blue dye. Credit: Beyaz lab/CSHL

Engineered immune cells slow tumor growth

But could these "leaner" immune cells kill diseased cells in human colorectal cancer? To find out, the lab activated PPARD in synthetic immune cells called CAR T cells. They then tested the PPARD-activated CAR T cells on organoids—miniature tumors grown from patient tissue samples. They also ran tests on human cancer cells in a dish and those implanted in mice.

In each case, Beyaz's team found that PPARD-activated CAR T cells slow or stop tumor growth. Notably, CAR T cells are already used in some cancer immunotherapies.

Extending the approach beyond colorectal cancer

The team initially focused on colorectal cancer because of how many young people die of it each year. However, they validated their results in other tumor types, including breast cancer, ovarian cancer and melanoma. Beyaz believes their findings are the "tip of the iceberg" in opening new inroads to make cancer immunotherapy more effective.

"Boosting immune cell fitness may also help with other conditions where the immune system fails to clear diseased cells," Beyaz says. His lab is now applying this approach to endometriosis, a chronic inflammatory disease affecting one in 10 women. Like colorectal cancer, it lacks effective treatment.

In a sense, Beyaz says, PPARD is not unlike "the force" from "Star Wars." It can promote disease, like Darth Vader carrying out the will of the Emperor. Or, like Anakin Skywalker, it can see the light and kill the disease. "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."

Publication details

Paul Bunk et al. Compartment-specific PPARδ activity determines the outcome of cancer–immune cell competition and immunotherapy efficacy, Nature Immunology (2026). DOI: 10.1038/s41590-026-02685-2. www.nature.com/articles/s41590-026-02685-2

Journal information: Nature Immunology

Key medical concepts

Colorectal Cancertumor growth

Clinical categories

OncologyAllergy and immunologyWomen's health Provided by Cold Spring Harbor Laboratory Who's behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →

Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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