Comprehensive Analysis of ATF3 as a Diagnostic and Prognostic Biomarker from Pan-Cancer to Clear Cell Renal Cell Carcinoma

Background: ATF3 was found to play a complex role in various cancers; however, its systematic function in kidney renal clear cell carcinoma (KIRC) and across pan-cancer contexts remained incompletely understood. Methods: A comprehensive evaluation of ATF3 expression, diagnostic efficacy, prognostic relevance, and its association with the tumor immune microenvironment was conducted across multiple cancer types using publicly available databases. In KIRC, ATF3 expression in cell lines was validated through real-time quantitative PCR, Western blot, and immunofluorescence tests. Assessments of immune cell infiltration and functional enrichment studies were also carried out. Ultimately, single-cell RNA sequencing (scRNA-seq) were implemented to clarify the role of ATF3 at the cellular level in KIRC. Results: ATF3 expression was observed to be downregulated in most cancers and was shown to possess diagnostic and prognostic value. Experimentally, ATF3 was confirmed to be downregulated in KIRC cell lines. In KIRC, higher ATF3 expression was connected with an improved outcome. Functional analyses indicated that ATF3 was involved in the IL-17 signaling pathway. The analysis demonstrated that, among seven immune cells with markedly varying infiltration levels, naive B cells and resting memory CD4 T cells were more prevalent in the ATF3 high expression cohort. ScRNA-seq analyses identified endothelial-afferent/efferent arterioles/descending vasa recta (AEAs/DVR) as the key cell, with ATF3 expression primarily detected during the early stage of AEAs/DVR differentiation. Conclusion: ATF3 was found downregulated in many cancers and proposed as a pan-cancer biomarker; in KIRC, its low level predicted poor outcome, indicating a potential immunotherapy target.