Hexokinase 3 dysfunction promotes tumorigenesis and immune escape by upregulating monocyte/macrophage infiltration into the clear cell renal cell carcinoma microenvironment

Abstract

<b>Purpose:</b> This study aimed to identify the potential prognostic role of HK3 and provide clues about glycolysis and the microenvironmental characteristics of ccRCC. <b>Methods:</b> Based on the Cancer Genome Atlas (TCGA, n = 533) and Gene expression omnibus (GEO) (n = 127) databases, real-world (n = 377) ccRCC cohorts, and approximately 15,000 cancer samples, the prognostic value and immune implications of HK3 were identified. The functional effects of <i>HK3</i> in ccRCC were analyzed <i>in silico</i> and <i>in vitro</i>. <b>Results:</b> The large-scale findings suggested a significantly higher <i>HK3</i> expression in ccRCC tissues and the predictive efficacy of <i>HK3</i> for tumor progression and a poor prognosis. Next, the subgroup survival and Cox regression analyses showed that <i>HK3</i> serves as a promising and independent predictive marker for the prognosis and survival of patients with ccRCC from bioinformatic databases and real-world cohorts. Subsequently, we found that <i>HK3</i> could be used to modulate glycolysis and the malignant behaviors of ccRCC cells. The comprehensive results suggested that <i>HK3</i> is highly correlated with the abundance of immune cells, and specifically stimulates the infiltration of monocytes/macrophages presenting surface markers, regulates the immune checkpoint molecules PD-1 and CTLA-4 of exhaustive T cells, restrains the immune escape of tumor cells, and prompts the immune-rejection microenvironment of ccRCC. <b>Conclusion:</b> In conclusion, the large-scale data first revealed that <i>HK3</i> could affect glycolysis, promote malignant biologic processes, and predict the aggressive progression of ccRCC. <i>HK3</i> may stimulate the abundance of infiltrating monocytes/macrophages presenting surface markers and regulate the key molecular subgroups of immune checkpoint molecules of exhaustive T cells, thus inducing the microenvironmental characteristics of active anti-tumor immune responses.