The Role of DNA Methylation in Osteosarcoma Pathogenesis and Therapy

Osteosarcoma (OS) is a highly malignant bone tumor primarily affecting children and adolescents. Clinical treatment has consistently encountered challenges, including chemotherapy resistance, high recurrence rates, and metastasis. Research has demonstrated that epigenetic regulation, particularly DNA methylation, can stably modify the DNA sequence without altering it, playing a key role in the development and progression of OS. Compared with normal tissue, OS exhibits distinctive alterations in DNA methylation, characterized by genome-wide hypomethylation and hypermethylation of specific gene promoter regions. This "dual pattern" not only promotes tumor proliferation, invasion, and metastasis but also maintains cancer stem cell characteristics and modulates the tumor immune microenvironment (TIME). Molecular classification based on DNA methylation profiles offers a new tool for the diagnosis and prognosis of OS. Drugs targeting DNA methylation, such as decitabine, have shown promising results for reversing gene silencing and suppressing tumor progression. This article systematically reviews the core mechanisms by which DNA methylation contributes to OS development, progression, and metastasis, and examines its potential for clinical translation.