Hexokinase 3 Dysfunction Promotes Tumorigenesis and Immune Escape by Regulating Monocyte/Macrophage Infiltration of Clear Cell Renal Cell Carcinoma Microenvironment

Purpose: This study aims to identify potential prognostic role of ccRCC and provide clues for glycolysis and the benefits of immune checkpoint therapies (ICTs) of ccRCC. Methods: Based on TCGA (n=533), GEO (n=118), real-world (n=377) ccRCC cohorts, and approximately 15,000 cancer samples, prognostic value of HK3 was identified using survival, Cox regression and ROC analysis. Afterwards, functional effects of HK3 in ccRCC were analyzed in silico and in vivo. Results: The large-scale findings suggested significantly higher HK3 expression in ccRCC tissues and the predictive efficacy of HK3 for tumor progression and poor prognosis. Next, the subgroup survival and Cox regression analysis found that HK3 serves as a promising and independent marker predicting prognosis and survival of ccRCC patients from bioinformatics and real-world cohorts. Subsequently, we found that HK3 could modulate malignant behaviors of ccRCC cells. Additionally, the comprehensive results suggested that HK3 highly correlated with abundance of immune cells, and specifically stimulates the infiltration of monocyte/macrophage surface markers, regulates the immune checkpoint molecules PD-1 and CTLA-4 of exhaustive T cells, affects the immune escape process of cancers and predicts outcomes for ccRCC patients receiving ICT. Conclusion: In conclusion, the large-scale data first revealed that HK3 could predict aggressive progression and poor prognosis of ccRCC, and improve predictive outcomes for ccRCC patients receiving ICT. HK3 activated ccRCC microenvironment stimulates the abundance of monocyte/macrophage surface markers infiltration, and may regulate the key molecular subgroups immune checkpoint molecules of exhaustive T cells, promoting the formation of tumor immune escape in cancers. Funding Statement: This work is supported by Grants from National Key Research and Development Project (No.2019YFC1316000), the Natural Science Foundation of Shanghai (No.20ZR1413100) and Shanghai Municipal Health Commission Project (2020CXJQ03) Declaration of Interests: The author reports no conflicts of interest in this work. Ethics Approval Statement: The Ethics approval and participation consent of this study was approved and agreed by the ethics committee of Fudan University Shanghai Cancer Center (Shanghai, China).