The evolving landscape of the Warburg effect in gastric cancer: From molecular mechanisms to targeted therapy

Abstract

Background: Gastric cancer (GC) remains a major health burden because of late-stage diagnosis and resistance to systemic therapy.

Main body: In GC, the Warburg effect is driven by interconnected hypoxia and oncogenic signalling, non-coding RNA networks and transcriptional and epigenetic rewiring. These regulators converge on glucose transport and core glycolytic enzymes, including HK2, PFKFB3, PKM2 and LDHA. The resulting increase in aerobic glycolysis, pyruvate-to-lactate conversion and lactate export supports biosynthesis, redox homeostasis and survival under metabolic stress. Beyond its bioenergetic role, lactate acts as a signalling metabolite that acidifies and remodels the tumour microenvironment. It impairs CD8-positive T and natural killer cells function, promotes regulatory T cells accumulation and M2 macrophages polarisation, activates stromal cells and facilitates epithelial–mesenchymal transition and immune evasion. Together, tumour-intrinsic metabolic adaptation and lactate-mediated microenvironmental reprogramming contribute to resistance to chemotherapy, targeted therapy and immunotherapy. Translationally, metabolic imaging, circulating LDH and lactate-related markers, exosomal glycolytic enzymes, gene-expression signatures and lactylation-related features may improve prognostic assessment, treatmentresponse prediction and patient stratification. These findings support biomarker-guided combination strategies that target tumour metabolism, lactate production or transport and stromalimmune crosstalk alongside standard therapies. This review uniquely integrates direct GC-derived evidence with indirect evidence from non-GC models and clinical trials and grades biomarkers and metabolic interventions according to their translational maturity.

Conclusion: Overall, the Warburg effect represents both a central driver of GC progression and a clinically relevant metabolic vulnerability.

Keywords

gastric cancer / glycolysis / metabolic heterogeneity / targeted therapy / Warburg effect

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