New Mechanism Discovered: How Liver Cancer Cells Evade Immune Cell Attacks

- Research team led by Professor Seok-Woo Nam at The Catholic University of Korea College of Medicine identifies how liver cancer cells evade macrophage-mediated immune responses -

- Link between RNA regulation and macrophage function revealed… opening new possibilities for immunotherapy -

[Photo] Professor Seok-Woo Nam (corresponding author) and doctoral student Jin-Woong Ha (first author) from the Department of Pathology, The Catholic University of Korea College of Medicine

A research team led by Professor Seok-Woo Nam (corresponding author) at the Department of Pathology, The Catholic University of Korea College of Medicine, has uncovered a novel process by which RNA regulatory abnormalities within liver cancer cells alter the function of surrounding macrophages, ultimately allowing the cancer cells to evade immune attacks. The findings were published in the international journal *Cancer Communications* (Impact Factor: 28.4).

Macrophages are vital innate immune cells that identify, engulf, and eliminate abnormal cells—such as bacteria, dead cells, and cancer cells—within the body. However, cancer cells have developed various ways to evade macrophage attacks; in some cases, they even manipulate macrophage function to their own advantage.

▲ A new method by which liver cancer cells neutralize macrophages

The research team discovered that an increase in the protein IGF2BP2—which regulates RNA—within liver cancer cells enhances the activity of MYBL2. This, in turn, leads to an increase in the expression and secretion of a protein called HMGB2.

Specifically, the HMGB2 secreted by liver cancer cells transmits signals to surrounding macrophages via the RAGE receptor, impairing the macrophages' ability to engulf and eliminate cancer cells. The properties of macrophages also shifted in a way that favored the survival of cancer cells.

The research team verified these findings through a multi-step approach, moving beyond mere genomic analysis or cell-based experiments to include functional assays using actual human liver cancer tissue and macrophages, as well as animal models of liver cancer.

▲ From "Don’t eat me" signals to the regulation of macrophage function

A well-known mechanism by which cancer cells evade attacks from macrophages involves the CD47–SIRPα signaling pathway. In this process, CD47 molecules on the surface of cancer cells send a "don’t eat me" signal to macrophages, effectively preventing their own destruction. Consequently, modulating such signals to reactivate the ability of macrophages to eliminate cancer cells has been a key area of research in cancer immunotherapy.

The research team discovered that dysregulated RNA control in liver cancer cells leads to an increase in the expression and secretion of HMGB2. This, in turn, alters the function of surrounding macrophages, enabling the cancer cells to evade the immune system.

▲ Can restoring macrophage function lead to new therapeutic approaches?

A therapeutically significant finding in this study is that inhibiting the HMGB2–RAGE signaling pathway—the mechanism by which liver cancer cells neutralize macrophages—restores the ability of these macrophages to eliminate cancer cells. Professor Nam Seok-woo explained, “The significance of this study lies not only in the identification of a specific protein as a new therapeutic target, but also in the discovery that dysregulated RNA control within cancer cells can alter the function of surrounding macrophages.” He added, “By restoring the normal function of macrophages—which have been abnormally altered by disease—we may uncover new therapeutic possibilities not only for cancer, but also for inflammatory and fibrotic diseases.”

NEORNAT, a biotech company founded by Professor Nam Seok-woo, is currently developing therapeutics that utilize RNA to regulate macrophage function.

[Figure] Schematic diagram of the research conducted by Professor Nam Seok-woo’s team