Fibrates in cholesterol drugs can stop liver cancers from recruiting 'traitor' immune cells, preventing immunotherapy resistance.

A commonly prescribed cholesterol drug may improve the effectiveness of liver cancer immunotherapy, according to researchers at the Fifth Affiliated Hospital at Sun Yat-sen University. 

Fibrates like fenofibrate (TriCor) are second-line triglyceride-reducing medications typically prescribed for people with severely elevated triglycerides or those who can’t tolerate first-line statin medications. The researchers hypothesized these and other drugs that help lower blood fat levels might help treat hepatocellular carcinoma, the most common type of primary liver cancer, because of their effect on a protein called phospholipid transfer protein (PLTP).

Immune checkpoint inhibitors are a class of immunotherapy drug that blocks the mechanisms tumors use to hide from the immune system. In liver cancer, however, tumors tend to respond poorly to these drugs. Studies have found that these tumors are able to recruit M2 macrophages, immune cells that suppress inflammation and promote healing, to help suppress cancer-fighting T-cells, which makes immune checkpoint inhibitors less effective.

Researchers believe that PLTP is actively involved in the process that turns macrophages into such “traitor” cells.

In the body, PLTP helps manage fat metabolism, but it also triggers inflammation and is associated with chronic conditions like heart disease. Recent research has linked it to the disease process that turns normal cells into cancerous cells, and some research has found that having too much PLTP can increase the risk of liver cancer in high-risk populations.

“Inside liver cancer cells, PLTP acts like a glue that sticks two proteins—P65 and AURKA—together,” said Linjuan Zeng, the study’s corresponding author. “This triggers a special ‘activation mark’ on P65, which turns the cancer cell into a broadcasting station that sends out strong signals to attract nearby immune guards (macrophages). Instead of attacking the tumor, these recruited guards are reprogrammed into a ‘traitor’ mode (called M2 macrophages). These traitor guards not only help the tumor grow and repair itself, but also throw heavy shackles onto the body’s elite killer T‑cells, preventing them from reaching and destroying the cancer.”

Liver cancer tumors produce PLTP in excess, likely because cancer cells need large amounts of lipids in order to support rapid growth and division, said Zeng. To meet the increased demand for lipids, and because PLTP helps cells move and manage fats, liver cancer cells appear to produce more of it.

The Sun Yat-sen University researchers found that fibrate drugs reduced PLTP levels in liver cancer cells, which made the tumors less able to recruit macrophages. Because of this, immune checkpoint inhibitors used in combination with fibrate drugs suppressed liver cancer growth more effectively than checkpoint inhibitors alone.

Confirming this concept, the researchers also tested an experimental drug called GMB-475 and found that it, too, helps suppress PLTP-driven M2 macrophages and improve sensitivity to immunotherapy, though the mechanisms are different.

“Importantly, fibrates are already approved for clinical use (as lipid‑lowering drugs) with well‑known safety profiles, whereas GMB‑475 is still an experimental compound,” said Zeng. “This makes fibrates a more readily translatable option for combination therapy.”

“This study offers a very important finding for overcoming immunotherapy resistance in liver cancer,” said Dr. Hongyu Zhang, Chief of the Cancer Center at the Fifth Affiliated Hospital of Sun Yat‑sen University, who was not involved in the research. “Since fenofibrate is already an approved drug, we are very much looking forward to the rapid advancement of clinical trials combining fenofibrate with immunotherapy to confirm its benefit in patients. I believe this is a highly promising approach.”

Since fibrates are already FDA-approved, the Sun Yat-sen University researchers plan to initiate human trials in liver cancer patients in the near future.

“We remain fully aware that the path requires careful, stepwise clinical development, not merely relying on the pre‑existing approval of the individual drugs,” Zeng said. “The combination of fibrates and [immune checkpoint inhibitors] is a new therapeutic entity that demands its own rigorous evaluation. We are actively working on trial protocols and regulatory submissions to address these very points.”

Before the research can move on to human studies, the researchers must first validate the role of PLTP and determine whether they can reliably predict which patients will benefit. They also need to overcome regulatory and financial barriers and ensure that metabolic side effects in test subjects are carefully managed.

Though the liver cancer work is still ongoing, the researchers believe that other cancers may also benefit from PLTP-targeted strategies.

“PLTP expression has been linked to disease progression in gastric cancer … and shown to be a core differential protein in HIV/HBV co-infected patients, suggesting a broader role in tumor biology,” Zeng said. “However, translating the combination of fibrate and immunotherapy to other cancers is not straightforward … In short, the liver cancer findings provide a strong rationale, but they cannot be automatically generalized without further investigation.”

Reference: Liang Xinyue, Zeng Linjuan et al., Fibrates Inhibit PLTP-induced M2 Macrophage Infiltration and Increase the Sensitivity of Hepatocellular Carcinoma to ICIs, Advanced Science (2026), DOI: 10.1002/advs.202513257.

Featured Image Credit: H.M. Adriaans (1854), courtesy of Leiden University Libraries