IER3 Promotes Malignant Progression of Colorectal Cancer Through the NF-κB 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 in vitro and in vivo. Mechanistically, IER3 activates the TNF-α/NF-κB 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.