CSHL Study Reveals How to Turn Immune Cells Against Colorectal Cancer

A study from Cold Spring Harbor Laboratory (CSHL) identifies a potential strategy to render immunotherapy effective against colorectal cancer, a disease that currently resists both chemotherapy and modern immune treatments. Published in Nature Immunology, the research suggests that a specific transcription factor, typically associated with promoting tumor growth, can be repurposed within the immune system to fight cancer.

The Role of Cell Fitness

Semir Beyaz, an Assistant Professor at CSHL, led the investigation based on the premise that the biological constraints governing cancer cells and immune cells are similar. "We hypothesized that the fitness determinants of cancer and our immune cells may not be so different," Beyaz stated. He explained that because both cell types operate under identical chemical and physical rules, they likely evolve along comparable paths regarding metabolic efficiency.

The team focused on Peroxisome proliferator-activated receptor delta (PPARD), a factor known for orchestrating fat metabolism in human cells. Using a mouse model of colorectal cancer, researchers discovered that while cancer cells possess their own PPARD mechanisms, activating this factor specifically on the immune side shifts the tumor environment from pro-cancer to anti-cancer. According to Beyaz, "What cells eat affects who they are. When immune cells burn more fat, they become more fit for fighting cancer."

Testing CAR T Cells

To determine if these metabolically enhanced immune cells could target diseased tissue in humans, the laboratory activated PPARD in Chimeric Antigen Receptor (CAR) T cells. These synthetic immune cells, already utilized in certain cancer therapies, were tested against organoids—miniature tumors derived from patient samples—as well as human cancer cells cultured in dishes and implanted in mice. In every scenario, the PPARD-activated CAR T cells successfully slowed or halted tumor growth.

Although the initial focus was on colorectal cancer due to its high mortality rate among people under 50, the findings were validated across other tumor types, including breast cancer, ovarian cancer, and melanoma. Beyaz described the results as the "tip of the iceberg" for improving cancer immunotherapy efficacy.

Broadening Treatment Horizons

The implications extend beyond oncology. Beyaz noted that boosting immune cell fitness might assist in treating conditions where the immune system fails to clear diseased cells. His lab is currently applying this approach to endometriosis, a chronic inflammatory condition affecting one in ten women that lacks effective treatment options.

Comparing the mechanism to popular culture, Beyaz likened PPARD to "the force" from Star Wars. It can either promote disease, akin to Darth Vader serving the Emperor, or combat it, like Anakin Skywalker turning to the light. "It's the classic fight between good and evil," Beyaz said. "How can good ultimately prevail? Activating PPARD in immune cells could be the way."

Journal Reference:

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