Multidimensional Roles of Deubiquitinases in Tumor Glycolytic Reprogramming

Tumor glycolytic reprogramming is an important metabolic hallmark of malignant tumors and plays a key role in sustaining tumor cell proliferation, adapting to microenvironmental changes, and promoting tumor progression. In recent years, deubiquitinating enzymes (DUBs), as important regulators of post-translational protein modification, have attracted extensive attention for their roles in tumor glycolytic reprogramming. Studies have shown that DUBs can not only directly affect glycolysis by regulating the stability and functional status of key glycolytic enzymes, glucose transporters, and upstream transcriptional regulators, but also indirectly regulate glucose metabolism through signaling pathways such as AMPK, mTOR, HIF-1, and PI3K/AKT. In addition, DUBs can participate in the interplay between tumor metabolism and the immune microenvironment by affecting lactate production in tumor cells, metabolic adaptation of immune cells, and immune checkpoint signaling. Notably, glucose metabolism-related products and changes in metabolic status can also reciprocally regulate the expression and function of DUBs through mechanisms such as lactylation, O-GlcNAcylation, and phosphorylation, suggesting that bidirectional feedback regulation may exist between the two. Drugs targeting DUBs have shown potential to interfere with glycolysis and inhibit tumor progression in some preclinical tumor models; however, their clinical translation still faces challenges, including context-dependent mechanisms of action, inhibitor selectivity, and safety. This article systematically reviews the molecular mechanisms by which DUBs regulate tumor glycolytic reprogramming, with a focus on their roles in metabolic signal transduction, interactions with the tumor immune microenvironment, and metabolic feedback regulation, and summarizes the research progress and existing issues in related targeted intervention strategies, aiming to provide new insights for mechanistic studies of tumor metabolic reprogramming and precision therapy.