Pan-cancer analysis identifies ANGPT4 as a potential prognostic biomarker associated with the tumor microenvironment in kidney renal clear cell carcinoma

As a pivotal member of the angiopoietin family, angiopoietin-4 (ANGPT4) is critically implicated in tumor initiation, progression, metastasis, and angiogenesis. However, systematic investigations into its impact on the tumor microenvironment (TME) and pan-cancer prognosis remain substantially lacking. Our comprehensive pan-cancer analysis and immunohistochemical results revealed that ANGPT4 expression was dysregulated across various cancers, with notably elevated levels in Kidney Clear Cell Carcinoma (KIRC) that were predictive of favorable clinical prognosis. Functional and gene set enrichment analyses revealed that ANGPT4 expression was positively correlated with diverse immune and stromal cell populations and inversely correlated with multiple tumor-promoting signaling pathways in KIRC. Furthermore, based on single-cell sequencing and spatial transcriptomic analyses, ANGPT4 expression was primarily detected in fibroblasts within the TME. Moreover, integrated computational analyses combining drug sensitivity profiling and Connectivity Map (CMap) screening revealed that three candidate compounds (clofibrate, MS.275, and AH.6809) were computationally predicted to reverse transcriptional signatures associated with ANGPT4 dysregulation in KIRC. In conclusion, we established ANGPT4 as a potential prognostic biomarker and a candidate molecule associated with the tumor microenvironment in KIRC.