Exosome-mediated metabolic-immune regulatory axis: mechanisms of gastric cancer progression and resistance and targeting strategies.

Gastric cancer (GC) is characterized by marked heterogeneity and frequent resistance to chemotherapy and immunotherapy. Exosomes mediate intercellular communication between tumor, stromal, and immune cells and may couple metabolic adaptation to immune suppression. This review synthesizes evidence for a bidirectional exosome-mediated metabolic-immune axis in GC. Tumor-derived exosomes enhance glycolytic and other metabolic programs, remodel macrophage and lymphocyte function, and promote immune escape, metastasis, and treatment resistance. Conversely, exosomes released by cancer-associated fibroblasts, tumor-associated macrophages, and mesenchymal stromal cells reinforce tumor-cell metabolism, stemness, survival, and chemoresistance. Together, these reciprocal interactions form a self-reinforcing circuit that links metabolic plasticity with an immunosuppressive microenvironment. We further evaluate circulating exosomal cargoes as candidate biomarkers for liquid biopsy and discuss therapeutic approaches involving inhibition of exosome biogenesis or uptake, combined metabolic and immune targeting, and engineered exosome delivery. Finally, we emphasize the limitations imposed by model systems, extracellular-vesicle heterogeneity, incomplete cell-type specificity, and inconsistent isolation and characterization methods. Defining reproducible, subtype-specific exosome-mediated interactions will be essential for translating this framework into clinically useful biomarkers and therapeutic strategies.