Metabolic-immune crosstalk in osteosarcoma: mechanisms and therapeutic opportunities.

Osteosarcoma (OS) is a highly aggressive primary bone malignancy that predominantly affects children and adolescents. Although surgical intervention and neoadjuvant therapy demonstrate efficacy in localized OS, postoperative survival rates remain suboptimal for patients with metastatic and recurrent OS. In recent years, immunotherapy has garnered considerable attention due to its promising efficacy across various solid tumors. However, the distinct immunosuppressive tumor microenvironment in OS restricts therapeutic response, as immunosuppressive states are further intensified in metastatic and recurrent lesions, thereby complicating immunotherapy efforts. Recent studies have found that metabolic reprogramming plays a crucial role in shaping the immunosuppressive tumor microenvironment of OS. Tumor cells can induce adaptive metabolic changes in immune cells through competitively consuming nutrients, accumulating immunosuppressive metabolites, and secreting exosomes. This subsequently diminishes their immune functions and promotes immune escape, which partially explains the poor efficacy of immunotherapy in OS. Thus, combining immunotherapy and metabolic-targeted drugs is a potential strategy for enhancing treatment efficacy against OS. This review focuses on the major characteristics of the immunosuppressive microenvironment in OS. It details how metabolic reprogramming in glucose, lipid, and amino acid metabolism remodels this environment and influences key immune cells, including tumor-associated macrophages (TAMs), T cells, and natural killer (NK) cells. It further explores the translational potential of combining metabolic interventions with immunotherapy to advance the clinical application in OS.