CUHK Researchers Uncover TREM2+ LAM Macrophage Mechanism Driving Liver Cancer Immunotherapy Resistance
Key Insights
A CUHK research team discovered that TREM2+ LAM (search) macrophages recycle fatty acids from apoptotic cells and deliver them to tumor cells via extracellular vesicles, fueling cancer survival.
Over 80% of advanced liver cancer (search) patients eventually develop resistance to immunotherapy, and TREM2+ LAM (search) was found significantly associated with poor prognosis in anti-PD-1 therapy.
In mouse models, combining a PD-1 inhibitor (search) with a TREM2 inhibitor (search) significantly reduced tumor size with no major side effects observed.
A research team from The Chinese University of Hong Kong (CUHK)'s Faculty of Medicine has identified a novel mechanism by which a specific macrophage subtype, TREM2+ LAM (search), drives resistance to immunotherapy in advanced liver cancer (search). The findings, published in the journal Cancer Cell, reveal a previously unknown "clear out–feed in" function in which these macrophages not only clear apoptotic cells but simultaneously recycle and deliver fatty acids to tumor cells, helping them evade immune attack.
Liver cancer (search) is the third leading cause of cancer-related deaths in Hong Kong, with most patients diagnosed at an advanced stage. For tumors that cannot be surgically removed, immunotherapy—specifically immune checkpoint blockade (ICB) therapy—is commonly used as a first-line treatment. However, even with a good initial response, over 80% of patients will eventually develop resistance to immunotherapy.
How TREM2+ LAM (search) fuels tumor resistance
Macrophages are highly adaptable immune cells that act as the body's "street sweepers," responsible for removing foreign particles, bacteria, and dead or apoptotic cells. The CUHK team, led by Professor Alfred Cheng Sze-lok from the School of Biomedical Sciences (SBS) at CU Medicine, found that in most liver cancer (search) patients treated with PD-1 inhibitors, TREM2+ LAM (search) increases within the tumor and is significantly associated with poor prognosis in patients undergoing anti-PD-1 therapy.
By analyzing tumor cells from liver cancer (search) patients who did not respond to anti-PD-1 therapy, the team observed that these tumor cells exhibited highly active fatty acid metabolism. Further studies in mouse models revealed that within the metabolically demanding tumor microenvironment, TREM2+ LAM (search) emerges as a macrophage subtype with strong lipid-processing capabilities. It "recycles" fatty acids from apoptotic cells and transports them via extracellular vesicles to cancer cells, providing nutrients and reprogramming gene expression in the tumor. This process helps tumor cells resist immune attack and enhances their resistance to immunotherapy.
Combination therapy shows promise in preclinical models
Dr. Liang Zhixian, Post-doctoral Fellow at the School of Biomedical Sciences, CU Medicine, described the team's subsequent experiments: "Building on these findings, our team conducted further experiments in mice. In cancer-bearing mice that were originally unresponsive to immunotherapy, a combination therapy of PD-1 inhibitor (search) and TREM2 inhibitor (search) was administered. After four weeks, the tumors in the mice were significantly reduced in size, and no behavioral changes or side effects related to body weight were observed, suggesting that this combination immunotherapy is safe and effective."
Path toward clinical translation
Professor Alfred Cheng Sze-lok confirmed that the team has applied for a patent on the use of TREM2+ LAM (search) in immunotherapy. "Our team is currently in discussions with the pharmaceutical sector to prepare for clinical studies, aiming to confirm the efficacy and safety of combination immunotherapy targeting TREM2+ LAM as a precision treatment. We expect to have results in two to three years," Cheng said.
The team estimates that combination immunotherapy targeting TREM2+ LAM (search) may help 40 to 50 percent of liver cancer (search) patients and might also benefit people with other cancers that have high levels of TREM2+ LAM. This discovery builds on the team's 2023 research, which first revealed that liver cancer cells can adapt to immunotherapy, resulting in resistance to ICB.