Abstract
Background/Objectives: Cellular senescence plays a critical role in tumorigenesis, immune cell infiltration, and treatment response. Adrenocortical carcinoma (ACC) is a malignant tumor that lacks effective therapies. This study aimed to construct and validate a senescence-related gene signature as an independent prognostic predictor for ACC and explore its impact on the tumor microenvironment, immunotherapy, and chemotherapy response. Methods: Data were collected from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Using Kaplan-Meier survival analysis, LASSO penalized Cox regression and multivariable Cox regression, we identified a prognostic model with four senescence-related genes (HJURP, CDK1, FOXM1, and CHEK1). The model's prognostic value was validated through survival analysis, risk score curves, and receiver operating characteristic (ROC) curves. Tumor mutation burden was assessed with maftools, and the tumor microenvironment was analyzed using CIBERSORT and ESTIMATE. Immune and chemotherapeutic responses were assessed through Tumor Immune Dysfunction and Exclusion (TIDE) and OncoPredict. Results: The risk score derived from our model showed a strong association with overall survival (OS) in ACC patients (p < 0.001, HR = 2.478). Higher risk scores were correlated with more advanced tumor stages and a greater frequency of somatic mutations. Differentially expressed genes (DEGs) that were downregulated in the high-risk group were significantly enriched in immune-related pathways. Furthermore, high-risk patients were predicted to have reduced sensitivity to immunotherapy (p = 0.02). Bioinformatics analysis identified potential chemotherapeutic agents, including BI-2536 and MIM1, as more effective treatment options for high-risk patients. Conclusions: Our findings indicate that this prognostic model may serve as a valuable tool for predicting overall survival (OS) and treatment responses in ACC patients, including those receiving chemotherapy and immunotherapy.