Decoding osteosarcoma pathogenesis: the pivotal influence of m⁶A modification

Osteosarcoma (OS) is the predominant primary malignant bone tumor in children and adolescents. Current treatments mainly include surgical resection combined with chemotherapy, but they still cannot effectively control tumor metastasis and recurrence, and may pose a risk of long-term complications. N6-methyladenosine (m⁶A) is the most widespread internal modification. It orchestrates various biological and disease-related events via the reversible m⁶A machinery comprising writers, erasers and readers. As a key epigenetic regulatory mechanism, m⁶A modification opens new avenues for deeper exploration of OS mechanisms and for developing new therapeutic targets and biomarkers. In this manuscript, we systematically explore the critical roles of m⁶A in OS cell proliferation, metastasis, metabolic reprogramming, programmed cell death, and tumor microenvironment regulation. Our aim is to provide a robust theoretical framework to underpin future basic studies and clinical applications in this field.