Immunotherapy and metabolic-targeted drug combination shows promise for osteosarcoma treatment

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Frontiers in Medicine Published June 5, 2026 Medically reviewed June 5, 2026 Study authors: Xihan Wan, Wenge He, Baicheng He, Liang Chen DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider that combining immunotherapy with metabolic-targeted drugs is an emerging but unproven strategy for osteosarcoma.

This narrative review examines the potential of combining immunotherapy with metabolic-targeted drugs as a treatment strategy for osteosarcoma, including metastatic and recurrent disease. The authors synthesize preclinical and early clinical evidence on metabolic reprogramming in glucose, lipid, and amino acid metabolism, suggesting that targeting these pathways could enhance the efficacy of immunotherapeutic approaches. The review highlights the interplay between tumor metabolism and immune evasion, proposing that metabolic interventions may improve immune cell function and overcome resistance. However, the authors note that the evidence is largely preclinical, and no pooled effect sizes or comparative clinical outcomes are reported. Limitations include the lack of primary clinical data, absence of a systematic search methodology, and no discussion of specific adverse events or safety profiles. The practice relevance is cautiously framed: while the combination strategy is conceptually promising, it remains investigational, and further rigorous clinical trials are needed before any clinical recommendations can be made. Clinicians should interpret these findings as hypothesis-generating rather than practice-changing.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

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.