Avoid, repair, tolerate: emerging mechanisms of MAP therapy resistance in osteosarcoma

Osteosarcoma is a rare but highly aggressive primary bone malignancy that predominantly affects children, adolescents, and young adults. Despite advances in surgery and supportive care, treatment has remained largely unchanged for more than four decades and continues to rely on the MAP regimen, comprising high-dose methotrexate, doxorubicin, and cisplatin. While MAP therapy improved survival for patients with localised disease, outcomes for metastatic, recurrent, or treatment-refractory osteosarcoma remain poor, primarily due to intrinsic and acquired chemotherapy resistance. In this review, we examine the canonical and non-canonical mechanisms of action of MAP chemotherapy and propose a unified framework for resistance based on three fundamental strategies: avoidance of damage, repair of damage, and adaptation to tolerate damage. Beyond established mechanisms involving altered drug transport, detoxification, and DNA repair, we highlight emerging evidence implicating replication stress tolerance, metabolic rewiring, epigenetic plasticity, transcription-associated stress responses, proteostasis, and innate immune signalling in therapy resistance. We further discuss how the marked genomic instability and heterogeneity of osteosarcoma may promote the evolutionary emergence of drug-resistant clones, and outline future approaches to identify novel therapeutic vulnerabilities and improve the clinical management of osteosarcoma.