Reduced FOXO1 expression is associated with tumor progression through metabolic and immune dysregulation in kidney renal clear cell carcinoma

Abstract

Kidney renal clear cell carcinoma (KIRC), the most aggressive subtype of renal cancer, is characterized by metabolic reprogramming and an immunosuppressive microenvironment. While forkhead box O1 (FOXO1) is recognized as a pleiotropic regulator of cellular metabolism and immune responses, its potential tumor-suppressive roles in KIRC remain undefined, particularly regarding metabolic–immune crosstalk. We integrated The Cancer Genome Atlas bulk RNA sequencing and clinical data, immunohistochemical validation (The Human Protein Atlas database), and bioinformatics algorithms (single-sample Gene Set Enrichment Analysis [GSEA] and GSEA). Survival modeling (Cox regression and Kaplan–Meier), differential gene expression profiling, and protein–protein interaction network construction were systematically performed to delineate FOXO1’s prognostic relevance and candidate associated mechanisms. Lower FOXO1 expression was associated with unfavorable overall clinical outcomes and more advanced pathology stages and histologic grades. Reduced FOXO1 expression was accompanied by an immunosuppressive tumor microenvironment, marked by elevated regulatory T cell infiltration and diminished effector and memory T cell signatures. Gene Ontology together with GSEA analyses showed a strong association between FOXO1 and lipid metabolism-related pathways. In addition, FOXO1 expression correlated with altered expression of epigenetic regulators, including higher lysine acetyltransferase 2A (KAT2A) and lower E1A-binding protein P300 (EP300), which may be associated with T cell functional states. This study, based on bulk RNA sequencing data and in silico analyses, suggests that FOXO1 could represent a potential regulator of metabolic–immune interactions in KIRC and is associated with tumor progression and remodeling of the immune landscape. Our results support that FOXO1 emerges as a potential indicator of patient prognosis. However, additional experimental studies are required to further substantiate these observations.