Metabolic reprogramming in the immune microenvironment of Ewing sarcoma: from mechanisms to therapeutic strategies

Ewing sarcoma is the second most common primary malignant bone tumor in children and adolescents, with the EWSR1-FLI1 fusion gene serving as its core driver event. Although multi-agent chemotherapy has achieved nearly 70% five-year survival in patients with localized disease, the prognosis for those with metastatic or relapsed/refractory disease remains poor, with long-term survival rates below 30%, and no substantial breakthrough has been made in first-line regimens over the past decade. Immune checkpoint inhibitors have revolutionized the treatment landscape for various adult solid tumors, but their efficacy in Ewing sarcoma—a typical “cold” tumor—is limited, owing to its low tumor mutational burden, sparse neoantigens, and highly immunosuppressive microenvironment. Recent studies suggest that EWSR1-FLI1 not only reshapes transcriptional programs but also functions as a metabolic “master switch, “ driving enhanced glycolysis, altered glutamine and tryptophan metabolism, and lipid metabolic remodeling. These metabolic alterations, in turn, produce lactate, kynurenine, lipid mediators, and local hypoxia, which suppress effector T cells and natural killer cells, induce regulatory T cells, and polarize macrophages toward a protumor phenotype, thereby forming a self-reinforcing causal chain between metabolism and immunity. This review systematically delineates this chain—from fusion-driven metabolic reprogramming, through metabolism-mediated immunosuppressive mechanisms, to intervention strategies targeting the metabolism–immunity interface. We focus on glycolysis inhibition, blockade of the tryptophan–AHR axis, lipid metabolism interventions, as well as novel surface targets (B7-H3, STEAP1, ENPP1, IL1RAP, MIF-CD74) for cell-based therapies and combination strategies of metabolic modulation with immunotherapy. We further analyze the practical obstacles to translating these strategies into clinical practice and, based on a critical synthesis of available evidence, Propose a metabolic–immune coupling model anchored on the active state of EWS-FLI1 to explain plasticity-driven resistance. This model provides a translational roadmap grounded in metabolic subtyping with the goal of “converting cold tumors to hot, “ offering a new framework for improving outcomes in Ewing sarcoma.