What does this research mean for the field?

Glycolytic reprogramming, driven by the dysregulation of key enzymes and hyperactive signaling pathways, is central to cancer progression and tumor microenvironment remodeling, presenting viable vulnerabilities for targeted cancer therapies. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

To systematically analyze the role of glycolytic reprogramming in cancer progression and evaluate therapeutic strategies targeting these metabolic changes.

June 21, 2026Open Access

The Warburg effect and beyond: Glycolytic reprogramming in cancer progression and emerging therapeutic strategies

Key Points

To systematically analyze the role of glycolytic reprogramming in cancer progression and evaluate therapeutic strategies targeting these metabolic changes.
Comprehensive review of the Warburg effect and its implications in cancer biology.
Analysis of key glycolytic enzymes and their dysregulation due to oncogenic pathways.
Evaluation of emerging therapeutic strategies targeting glycolysis-related vulnerabilities.
Increased glucose uptake and lactate production were linked to enhanced tumor progression and invasive behavior.
Key enzymes such as HK2, PKM2, and LDHA were found to be critical mediators of metabolic changes and tumor microenvironment reshaping.
Therapeutic strategies targeting HK2, G6PD, PFKFB3, and LDHA showed potential in overcoming glycolysis-related vulnerabilities.

Abstract

Metabolic reprogramming, especially the upretoning and functional reshaping of glycolysis, is the cornerstone of cancer progression, driving proliferation, invasion and metastasis. This review systematically analyzes the Warburg effect. This metabolic transformation promotes the progression of malignant tumors by enhancing glucose uptake, lactate production and microenvironmental remodeling. We elaborated on the molecular basis of this process, focusing on the oncogenic dysregulation of key glycolytic enzymes such as hexokinase 2 (HK2), phosphofructose kinase-1, pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). These malfunctions are usually driven by hyperactive signaling pathways such as PI3K/AKT/mTOR and HIF-1α. This metabolic remodeling also actively shapes the tumor microenvironment (TME) by promoting acidosis, inhibiting anti-tumor immunity and stimulating angiogenesis. Intermediate metabolites in the process of glycolysis can also be used as signal nodes to regulate epithelial-mesenchymal transition (EMT) and maintain the plurity of cancer stem cells (CSC). The cyclic flux of the pentose phosphate pathway (PPP) and the truncated tricarboxylic acid (TCA) cycle flux further highlight the metabolic flexibility inherent in malignant cells. Finally, we critically evaluated emerging treatment strategies for these glycolysis vulnerabilities, including inhibitors of HK2, glucose-6-phosphate dehydrogenase (G6PD), fructose-2,6-diphosphatase3 (PFKFB3) and LDHA. This review reinforces the central position of glycolysis metabolism and emphasizes the potential of tumor treatment.

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Cite This Study

Long et al. (Fri,) studied this question.

synapsesocial.com/papers/6a377fdd24f042ddf4c5a1c6 https://doi.org/https://doi.org/10.1016/j.biopha.2026.119692

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