ERMP1 Exerts Tumor‐Suppressive Functions in KIRC by Inhibiting PI3K/AKT Signaling and Remodeling the Immune Microenvironment: A Pan‐Cancer Analysis

Background Kidney renal clear cell carcinoma (KIRC) is an aggressive malignancy with limited therapeutic options, highlighting the need for novel biomarkers and therapeutic targets. Although endoplasmic reticulum metallopeptidase 1 (ERMP1) has been implicated in cancer progression, its specific role, clinical significance, and underlying mechanisms in KIRC remain poorly defined. Methods We integrated data from the TCGA, GTEx, and GEO databases to conduct a pan‐cancer analysis, aiming to systematically evaluate the expression patterns, genetic alterations, and prognostic value of ERMP1. Single‐cell transcriptomic data were utilized to decipher its cell‐type–specific expression within the tumor immune microenvironment. By establishing ERMP1 overexpression models in KIRC cell lines (Caki‐1 and A498), we assessed its impact on malignant phenotypes using CCK‐8, colony formation, transwell, and wound healing assays. The underlying mechanisms were further investigated via Western blotting. Finally, by establishing a xenograft tumor model in vivo, we evaluated the inhibitory effect of ERMP1 on tumor growth of KIRC in vivo. Results The prognostic value of ERMP1 exhibits cancer type‐specificity. In KIRC, its high expression serves as an independent marker for favorable prognosis and is negatively correlated with advanced pathological features. Single‐cell analysis revealed that ERMP1 is enriched in regulatory T cells and proliferative exhausted T cells. Its high expression is closely associated with an immunologically activated tumor microenvironment, characterized by upregulation of immunostimulatory factors and chemokines, alongside increased lymphocyte infiltration. Functionally, ERMP1 overexpression significantly suppressed the proliferation, migration, invasion, and clonogenic ability of KIRC cells. Mechanistically, ERMP1 inhibits the PI3K/AKT signaling pathway, impedes epithelial‐mesenchymal transition (manifested as E‐cadherin upregulation and N‐cadherin downregulation), and reduces the expression of invasion‐related proteins (MMP2 and MMP9) and cell cycle‐related proteins (Cyclin D1 and CDK4). In vivo xenograft tumor assays confirmed that ERMP1 overexpression could significantly inhibit tumor growth. Conclusion This study confirms that ERMP1 exhibits significant potential in tumorigenesis, diagnosis, prognosis, and regulation of the tumor microenvironment (TME). In KIRC, ERMP1 may exert tumor‐suppressive effects by inhibiting the PI3K/AKT signaling pathway and regulating immune responses, thus representing a potential prognostic biomarker and therapeutic target.