IER3 Promotes Malignant Progression of Colorectal Cancer Through the NF-B Pathway.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, primarily due to metastatic progression and an immunosuppressive tumor immune microenvironment (TIME). The stress-responsive gene IER3 is found to be dysregulated in multiple cancers. Currently, its functional role in CRC pathogenesis and immune modulation remains poorly understood. Here, using integrated single-cell RNA sequencing (scRNA-seq) of clinical samples, we identify a distinct IER3-expressing malignant subpopulation associated with aggressive disease and poor prognosis. Functional studies demonstrate that IER3 drives CRC proliferation, invasion, and metastatic capacity both and . Mechanistically, IER3 activates the TNF-/NF-B signaling pathway, thereby enhancing the expression and phosphorylation of RELA/p65. Moreover, IER3 malignant cells reshape the TIME into an immunosuppressive state by altering immune cell infiltration and promoting communication via the FN1-CD44 axis. High IER3 expression correlates with reduced response to immune checkpoint blockade (ICB) and distinct drug sensitivity profiles. Together, these findings confirm that IER3 is a dual critical mediator of CRC progression and immune escape, highlighting its potential as a therapeutic target and biomarker for personalized treatment strategies.