EGR1 lactylation induces tumor cell senescence and immunosuppressive microenvironment in intrahepatic...

Cellular senescence, which is a hallmark of cancer, has been gaining increasing attention in recent years. However, its role in immunosuppressive microenvironment of intrahepatic cholangiocarcinoma (iCCA) remains poorly understood.

We utilized publicly available bulk and single-cell transcriptomic datasets of iCCA to identify senescent tumor cells and the cell type composition within the immunosuppressive microenvironment. Then, the roles of senescent tumor cells and immunosuppressive cell types were verified through in vitro and in vivo experiments.

We defined a 101 iCCA senescence-related gene signature (ISG) to assess cellular senescence in iCCA. Higher ISG levels indicate a poorer prognosis and increased infiltration of immunosuppressive cell types. We observed that the ISG-high malignant subgroup exhibits low proliferation but high stemness. Meanwhile, the ISG-high malignant cells upregulated the hypoxia and glycolysis pathways. Furthermore, we identified the key transcriptional factor EGR1 and demonstrated its regulatory role in the expression of CDKN1A. Mechanistically, the K422 site of EGR1 undergoes lactylation, which promotes its nuclear translocation and further regulates the transcription of CDKN1A, ultimately leading to the induction of the senescence phenotype. Moreover, cell-cell interaction analysis revealed that ISG-high malignant cells recruited and regulated immunosuppressive MACRO⁺ tumor-associated macrophages through the LGALS9-CD44/THBS1-CD47 axis, and the immunosuppressive MACRO⁺ TAMs could also recruit Tregs through the CXCL12-CXCR4 axis, thereby forming an immunosuppressive microenvironment.

We defined a novel ISG signature in iCCA and identified EGR1 as a critical driver of senescent tumor cells in iCCA.These findings offer new insights into senescent tumor cells and the immunosuppressive microenvironment.