The JAK-STAT signaling-related signature serves as a prognostic and predictive biomarker for renal cell carcinoma immunotherapy.

ABSTRACT

Renal cell carcinoma (RCC) represents a significant portion of genitourinary cancers, marked by challenging prognosis and high metastasis rates. Immunotherapy has been applied in managing advanced renal cell carcinoma, but the therapeutic outcomes are unsatisfactory. In this study, we order to construct a Janus kinase/signal transduction and activator transcriptional (JAK/STAT)-related signature linked to kidney patient outcomes for better predicting the efficacy to immune checkpoint inhibitors (ICIs) and to provide guidance for effective combination therapy. We screened 25 differentially expressed genes (DEGs) that exhibited high expression in RCC samples and were enriched in the JAK-STAT signaling pathway. Among these genes, 11 key genes were identified and correlated with the expectation of Kidney Clear Cell Carcinoma (KIRC) patients and all these genes was significantly elevated in RCC tumor tissues and cancer cells compared to para-cancer tissues and normal renal cells. Utilizing these 11 genes, we divided RCC patients into high-risk and low-risk groups. We found a clear correlation between the clinicopathologic factors of KIRC patients and the JAK-STAT-related risk score. And the IHC results shown that the JAK3 and STAT4 expression of tumor was significantly higher than normal tissue in RCC patients, the level of JAK3 and STAT4 was positively related to the T stage of RCC patients. In addition, high-risk patients had a poorer prognosis and greater protumor immune cell infiltration, and benefitted less from immunotherapy than did low-risk patients. Furthermore, the JAK-STAT-related risk score can predict disease-free survival (DFS) in RCC patients according to the nomogram, which constructed in combination with other clinical features such as age, TNM-staging and stage. Our study demonstrated the JAK-STAT signaling pathway's important regulatory function in RCC tumor immunity. This insight not only enhances our ability to accurately predict the survival rate of RCC patients, but also underscores a potential therapeutic alternative for RCC, involving the combined targeting of the JAK-STAT pathway and immune checkpoints.