Why Targeting Tumor Sugar Addiction in Gastric Cancer Keeps Failing Clinically

Gastric cancer remains the fifth leading cause of cancer-related death worldwide, with China bearing a disproportionate burden. Current treatments—surgery, chemotherapy, and the emerging perioperative durvalumab-FLOT (MATTERHORN) regimen—offer modest survival gains but fall short in advanced disease. This review by Meng and colleagues asks a pointed question: why, after decades of mechanistic progress, has targeting cancer's sugar-burning metabolism failed to produce a single approved drug for gastric cancer?

The authors begin by cataloging the glycolytic machinery that makes gastric cancer cells so metabolically distinctive. Rate-limiting enzymes—hexokinase 2 (HK2), its compensatory isozyme HKDC1, pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), enolase 1 (ENO1), and phosphoglycerate kinase 1 (PGK1)—are consistently overexpressed and correlate with TNM stage, lymph node metastasis, and poor prognosis. These enzymes are not isolated actors; they operate within oncogenic signaling webs anchored by PI3K/AKT/mTOR and HIF-1α, which together enforce a glycolytic phenotype even in oxygen-replete environments. Helicobacter pylori infection, a primary gastric cancer risk factor, feeds directly into this circuitry: its virulence protein CagA activates PI3K/AKT and stabilizes HIF-1α, while simultaneously inducing HKDC1 via TGF-β/Smad2 signaling—linking chronic infection to metabolic reprogramming.

The review then systematically diagnoses why clinical translation has stalled. Three fundamental roadblocks are identified. First, temporal metabolic plasticity: when glycolysis is blocked at one node, cancer cells rapidly upregulate oxidative phosphorylation, the pentose phosphate pathway, or alternative hexokinase isoforms—essentially rerouting around the blockade within hours to days. PKM2's conformational switch between high-activity tetramer and low-activity dimer exemplifies this dynamic adaptability, shunting metabolites toward biosynthesis rather than energy production when needed. Second, spatial metabolic heterogeneity: different tumor regions and distinct cancer cell subpopulations harbor divergent metabolic dependencies, meaning a therapy effective against one metabolic subclone may be irrelevant or even advantageous to another. Third, a biomarker void: without validated predictive or pharmacodynamic biomarkers, clinical trials cannot enrich for responsive patients, monitor target engagement, or distinguish primary resistance from inadequate drug exposure.

Against these obstacles, the authors propose an integrated framework operating on two fronts. Diagnostically, spatial multi-omics (combining spatial transcriptomics, metabolomics, and proteomics) would enable high-resolution metabolic cartography of tumors, while AI-driven integrative platforms would translate this complexity into actionable patient stratification. Therapeutically, strategies include dual-pathway inhibition to pre-empt compensatory rerouting, exploitation of enzymes' non-catalytic 'moonlighting' functions (such as PKM2's nuclear signaling roles), tumor-penetrating nanocarriers for targeted metabolic drug delivery, and—most prominently—rational combination of glycolysis inhibitors with immunotherapy. Lactic acid secreted by glycolytically active tumors suppresses T-cell function and promotes regulatory T-cell accumulation; blocking lactate production or export could simultaneously starve the tumor and reinvigorate anti-tumor immunity. The review also highlights the metabolism–epigenetics axis: lactate-mediated histone lactylation and α-ketoglutarate-dependent DNA demethylation represent emerging nodes where metabolic and epigenetic reprogramming converge, offering additional combination targets.

The authors conclude that the paradigm must shift from static inhibition of single metabolic enzymes toward dynamic, network-level intervention guided by spatial diagnostics and mechanism-matched combination regimens. They frame this as the essential prerequisite for advancing precision metabolic medicine in gastric cancer beyond its current impasse.