An aging-related gene signature, featuring Cdkn2a, predicts prognosis and immunotherapy response in uterine corpus endometrial carcinoma

Uterine corpus endometrial carcinoma (UCEC) is one of the three major malignant tumors of the female reproductive system, severely impacting the health and lives of young women. Cellular senescence is a hallmark of cancer and plays a role in tumor progression. This study aims to investigate the predictive and diagnostic value of aging-related genes (ARGs) in UCEC. Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) UCEC cohort were analyzed. Consensus clustering based on 432 ARGs stratified patients into subgroups. Differentially expressed genes (DEGs) were identified, and a prognostic risk model was constructed using LASSO-Cox regression. Immune infiltration, immunotherapy response, and drug sensitivity were evaluated. Functional validation of a key gene, CDKN2A (encoding P16), was performed using in vitro assays in Ishikawa cells. Patients were classified into three senescence clusters, with Cluster 3 showing the worst prognosis and an immunosuppressed phenotype. A novel 10-ARG risk signature was established and validated, effectively stratifying patients into high- and low-risk groups with distinct survival outcomes. The high-risk group exhibited an immunosuppressive microenvironment, altered immune checkpoint expression, and differential sensitivity to chemotherapy agents. CDKN2A was upregulated in UCEC tissues, and its knockdown significantly inhibited cell proliferation, migration, and promoted apoptosis in vitro. The novel ARGs signature is a promising biomarker for predicting the outcome of UCEC and has the potential to guide immunotherapy. As one of ARGs, Cdkn2a may be a potential diagnostic and therapeutic target for UCEC.