Involvement of TP53 in osteosarcoma - challenges and prospects

Osteosarcoma (OS), the most common primary malignant bone tumor, remains a therapeutic challenge because of its high metastatic potential, chemoresistance, and poor prognosis. Mutations in the TP53 tumor suppressor gene, including loss-of-function (LOF) and gain-of-function (GOF) mutations, play a central role in OS progression by disrupting cell cycle regulation, DNA repair, and apoptosis and promoting immune evasion and metabolic reprogramming. This review provides an in-depth analysis of p53 biology in OS, highlighting its impact on therapeutic resistance and tumor progression. We discuss advancements in radiotherapy, chemotherapy, and immunotherapy, emphasizing strategies targeting mutant TP53 and its associated pathways. Emerging approaches, including metabolic reprogramming, noncoding RNA regulation, and precision biomarkers such as miRNAs and histone modifications, offer promising tools for diagnosis, risk stratification, and treatment optimization. By linking the molecular mechanisms of p53 with novel therapeutic strategies, this review underscores opportunities for translational research aimed at improving the clinical outcomes of OS patients.