Glycolysis‑driven immunosuppression in gastric cancer: Metabolic crosstalk between tumor cells and the immune microenvironment (Review).

Gastric cancer (GC) remains a major cause of cancer‑related mortality worldwide, and only a subset of patients achieves durable benefit from immune checkpoint blockade (ICB). This suggests that non‑genomic barriers within the tumor microenvironment (TME) substantially limit antitumor immunity. Increasing evidence indicates that tumor‑intrinsic glycolytic reprogramming and lactate accumulation contribute to this immune resistance. Oncogenic signaling, hypoxia‑inducible factor‑1α (HIF‑1α), phosphoinositide 3‑kinase/protein kinase B/mechanistic target of rapamycin (mTOR) pathways and noncoding RNA networks promote the expression of glycolytic enzymes and lactate transporters, including hexokinase 2, 6‑phosphofructo‑2‑kinase/fructose‑2,6‑biphosphatase 3 (PFKFB3), pyruvate kinase M2, lactate dehydrogenase A (LDHA) and monocarboxylate transporters, thereby establishing a glycolysis‑high, lactate‑rich TME. Within this metabolic niche, lactate functions as a bioactive mediator that impairs dendritic cell differentiation and cross‑priming, weakens cytotoxic T‑cell and natural killer‑cell activity, and promotes M2‑like macrophages and myeloid‑derived suppressor cells through hydroxycarboxylic acid receptor 1/G protein‑coupled receptor 81‑dependent signaling and histone lactylation. Cancer‑associated fibroblasts and mesenchymal stem/stromal cells further reinforce this state through glycolysis, lactate shuttling, cytokine secretion, extracellular matrix remodeling and exosome‑mediated transfer of glycolysis‑promoting noncoding RNAs. These interactions generate spatially organized immunometabolic niches characterized by lactate accumulation, stromal remodeling, abnormal angiogenesis and poor CD8