Deciphering mitotic catastrophe–associated transcriptomic patterns to predict prognosis and immunotherapy response in renal cell carcinoma

Background Renal cell carcinoma (RCC) is a highly heterogeneous malignancy with complex molecular features. Mitotic catastrophe (MC), a key regulator of cell fate during aberrant mitosis, contributes to tumor progression and therapeutic response; however, its prognostic relevance in RCC remains unclear. Methods We integrated multi-omics, clinical, and imaging data from TCGA and multiple external cohorts. Prognostic mitotic catastrophe–related genes were identified to construct a mitotic catastrophe–related score (MCRS) using CoxBoost and random survival forest models. Associations with clinicopathologic features, immune contexture, and mutational profiles were analyzed. Single-cell RNA sequencing characterized Cyclin F (CCNF) expression and its link to immunotherapy response, which was further validated through in vitro assays and murine xenograft models. Results A nine-gene MCRG signature stratified patients into high- and low-risk groups with strong prognostic performance (TCGA 1-, 3-, 5-year AUCs >0.9). High MCRS correlated with advanced stage, adverse CT features, angiogenesis, inflammatory signaling, regulatory T-cell infiltration, and elevated LAG3/TIGIT expression. MTOR mutations were enriched in high-risk tumors. SurvSHAP(t) analysis identified CCNF as the top prognostic contributor. CCNF was upregulated in tumor tissues and enriched in proliferating cells and epithelial cells. High CCNF expression predicted worse survival and reduced immunotherapy benefit. Overexpression of CCNF promoted RCC cell proliferation, migration, invasion, and in vivo tumor growth, partly through mTOR pathway activation. Conclusions We established a robust MC-based prognostic model for RCC and identified CCNF as a key driver of tumor progression, immune suppression, and therapy resistance. CCNF may serve as a biomarker and therapeutic target in RCC, particularly for immunotherapy optimization.