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

Abstract

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.

Abstract as supplied by the indexing source. © the authors / publisher.