Abstract
Tumor glycolysis is a major promoter of carcinogenesis and cancer progression. Given its complex mechanisms and interactions, comprehensive analysis is needed to reveal its clinical significance and molecular features. On the basis of a well-established glycolysis gene expression signature, we quantified 8633 patients with different cancer types from the Cancer Genome Atlas (TCGA) and evaluated their prognostic associations. High tumor glycolytic activity correlated with inferior overall survival in the pan-cancer patients (hazard ratio: 1.70, 95% confidence interval: 1.20-2.40, P = 0.003). The prognostic value of glycolysis correlated with the molecular subtypes and was stable regardless of clinical parameters. The prognostic significance of glycolysis was validated using three independent datasets. In addition, genome, transcriptome, and proteome profiles were utilized to characterize the distinctive molecular features associated with glycolysis. Mechanistically, glycolysis fulfilled the fundamental needs of tumor proliferation in multiple ways. Exploration of the relationships between glycolysis and tumor-infiltrating immune cells showed that glycolysis enabled the immune evasion of tumor cells. Mammalian target of rapamycin (mTOR) inhibitors and dopamine receptor antagonists can effectively reverse the glycolytic status of cancers. Overall, our study provides an in-depth molecular understanding of tumor glycolysis and may have practical implications for clinical cancer therapy.