Long non-coding RNAs in osteosarcoma: multifaceted regulators of malignancy and therapeutic resistance

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents, with an annual incidence of approximately 3–4 cases per million. Despite advances in treatment, the 5-year survival rate remains low, ranging from 20 to 30%, and drops below 20% for patients with recurrence or metastasis. Chemoresistance, affecting 30–40% of patients, is a major contributor to treatment failure. The role of long non-coding RNAs (lncRNAs) in OS pathobiology has gained increasing attention, as they regulate critical processes such as tumor progression, chemoresistance, immune modulation, and metabolic reprogramming. This review synthesizes current evidence on osteosarcoma (OS)-associated long non-coding RNAs (lncRNAs), categorizing their functions into several key areas. lncRNAs act as oncogenic drivers, promoting malignant phenotypes through transcriptional regulation, ceRNA networks, and modulation of signaling pathways. They also play a crucial role in mediating chemoresistance or sensitivity to chemotherapy, influencing processes such as epithelial-mesenchymal transition (EMT), epitranscriptomic stabilization, metabolic adaptation, and DNA repair. Additionally, lncRNAs regulate the tumor immune microenvironment (TIME), impacting immune cell infiltration, cytokine signaling, and immune phenotype polarization, thereby contributing to immune evasion and tumor progression. Furthermore, lncRNAs are involved in metabolic reprogramming, particularly in glycolysis and lipid metabolism, which supports tumor growth and survival. Emerging evidence highlights specific lncRNAs, such as circadian rhythm-related RP11-414H17.5 and SATB2-AS1, as potential prognostic biomarkers and therapeutic targets, which could help overcome drug resistance, modulate immunity, and disrupt tumor metabolism. Despite promising preclinical findings, the translation of lncRNA-based strategies into clinical practice is limited by small cohort sizes, lack of multi-center validation, and inconsistent detection methods. Future research should focus on integrating multi-omics and spatial transcriptomics for comprehensive lncRNA profiling, validating their functions in immunocompetent and patient-derived models, and exploring combination strategies with chemotherapy, immunotherapy, and metabolism-targeting drugs. A deeper mechanistic understanding and robust clinical validation will enable lncRNA-guided precision oncology, offering new avenues for personalized diagnosis and treatment in osteosarcoma.