Targeting Glycolytic Metabolism in Cancer Therapy: Current Approaches and Future Perspectives

TL;DR

This paper reviews how targeting cancer cell metabolism through glycolysis inhibition could improve cancer treatment, but highlights challenges like toxicity and the need for selective therapies.

Contribution

The paper provides a comprehensive review of glycolytic pathway targets, their inhibitors, and combination strategies to enhance cancer therapy.

Findings

Glycolytic enzymes like HK2, PFK, and PKM2 are promising targets for cancer therapy due to their role in the Warburg effect.

Monotherapy with glycolysis inhibitors faces limitations due to toxicity and tumor metabolic plasticity.

Combination therapies with glycolysis inhibitors and other treatments may overcome resistance and improve efficacy.

Abstract

Targeting the Warburg effect (aerobic glycolysis) in tumor cells represents a promising metabolic therapeutic strategy in cancer research. This review analyzes the regulatory mechanisms and therapeutic potential of key glycolysis pathway components, including glucose transporters (GLUTs) and glycolytic enzymes such as hexokinase 2 (HK2), phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA). We evaluate the molecular mechanisms of various inhibitors and the current clinical development landscape, noting that limitations of monotherapy stem not only from tumor metabolic plasticity but also largely from the unacceptable toxicity of many inhibitors due to the essential role of glycolysis in normal cell metabolism. Furthermore, we explore the molecular basis of synergistic interactions between glycolysis inhibitors and chemotherapy, radiotherapy, immunotherapy, photothermal therapy, and targeted therapy, proposing that rational combination strategies may help overcome resistance and improve therapeutic efficacy. Finally, the review outlines future challenges and directions, emphasizing that the primary obstacle in metabolic treatments is achieving selective inhibition of glycolytic enzymes in cancer cells while sparing normal cells. To address this challenge, the development of high-selectivity agents, cancer-specific nanodelivery systems, precise biomarker identification, and innovative combination regimens based on metabolic-immune regulation is crucial for advancing glycolysis-targeted therapy toward clinical translation.

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