Targeting Glycolytic Reprogramming in Gastric Cancer: Navigating the Translational Maze from Mechanism to Clinic

Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide. Among its defining hallmarks, metabolic reprogramming, particularly aerobic glycolysis (the Warburg effect), emerged as a central driver of tumor progression, therapeutic resistance, and immune evasion. Over the past decades, substantial efforts have delineated the molecular architecture of metabolic reprogramming in GC, identifying key effector enzymes, including hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA), as well as upstream oncogenic signaling axes, such as the PI3K/AKT/mTOR pathway and hypoxia-inducible factor 1-alpha (HIF-1α), along with their interconnected regulatory networks. Despite extensive preclinical validation of these nodes, clinical translation remains elusive, with glycolysis-targeted monotherapies showing limited efficacy in early-phase trials. Yet, we contend that this persistent translational failure does not stem from invalid targets, but rather from a systemic underestimation of three fundamental roadblocks: (1) temporal metabolic plasticity that enables rapid compensatory adaptation and pathway switching; (2) spatial inter- and intra-tumoral metabolic heterogeneity that undermines uniform treatment strategies; and (3) a critical void in predictive and pharmacodynamic biomarkers essential for patient stratification and treatment monitoring. To overcome these barriers, we propose an integrated, forward-looking strategic framework that converges advanced diagnostics with next-generation therapeutic modalities. On the diagnostic front, we highlight spatial multi-omics for high-resolution metabolic cartography and artificial intelligence-driven integrative patient stratification to map heterogeneity and predict treatment response. On the therapeutic front, we examine strategies designed to circumvent metabolic plasticity, including dual-pathway inhibition, nodal targeting, exploitation of non-catalytic vulnerabilities, and tumor-penetrating nanocarriers for targeted metabolic intervention. Particular emphasis is placed on rational, mechanism-driven combination regimens, especially those synergizing glycolysis-targeted therapies with immunotherapy to remodel the suppressive tumor microenvironment—as well as hierarchical and parallel pathway combinations and the emerging metabolism–epigenetics axis, exemplified by lactate-mediated histone lactylation and α-ketoglutarate-dependent DNA demethylation. By shifting the therapeutic paradigm from static inhibition of single metabolic nodes toward dynamic, network-level intervention, this review provides a strategic roadmap for translating the vulnerabilities inherent in the glycolytic network into durable clinical benefit for patients with GC. This paradigm shift, we argue, is essential for advancing precision metabolic medicine beyond the current impasse.