Study identifies how neutrophils evade ferroptosis in liver cancer, offering a potential way to boost immunotherapy

Researchers have identified how neutrophils that drive immune evasion in liver cancer survive by evading ferroptosis. They said targeting this mechanism could improve the effects of immunotherapy.

A team led by professors Wu Jian, Zheng Shusen and Chen Jianzhong at Zhejiang University in China published the findings on the 7th (local time) in the international journal GUT.

Hepatocellular carcinoma (HCC) is characterized by an immunosuppressive tumor microenvironment and is a representative cancer in which immune checkpoint inhibitor treatment has limited efficacy. Tumor-associated neutrophils (TANs) are considered key regulators that promote cancer progression.

Although neutrophils are vulnerable to ferroptosis, an iron-dependent and lipid-dependent form of cell death, they continue to accumulate in tumors. The researchers focused on this paradox and investigated how neutrophils evade ferroptosis.

They found that tumor-associated neutrophils highly expressed TREM2, a lipid-sensing receptor. The bioactive lipid S1P released by tumors activated the TREM2-NRF2 axis, increasing anti-ferroptosis genes such as GPX4 and allowing neutrophils to survive and maintain their immunosuppressive function.

TREM2 expression was induced by tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) through STAT3 phosphorylation. Together with S1P signaling, this activated the PI3K-AKT-NRF2 pathway and increased anti-ferroptosis genes such as GPX4 and SLC7A11.

When the researchers deleted the TREM2 gene or blocked S1P synthesis by inhibiting SPHK1/2 in tumor cells, ferroptosis in neutrophils increased substantially. The tumor immune microenvironment was remodeled, and cancer progression slowed.

Genetic deletion or peptide-based inhibition of TREM2 also reduced immunosuppressive neutrophils and enhanced the killing capacity of CD8⁺ T cells. In mouse liver cancer models, combining either approach with PD-1 blockade produced greater tumor suppression.

The researchers said the findings identify a metabolic checkpoint that protects neutrophils from ferroptosis and open a new therapeutic opportunity to overcome immune evasion in liver cancer by targeting the S1P-TREM2 axis.