Early signs of progress in osteosarcoma research

In the past two decades, the only agent to have become available for osteosarcoma, the most common primary bone cancer in adolescents and young adults, is mifamurtide, a macrophage-activating immune modulator approved in Europe for patients under 30 years of age with high-grade resectable non-metastatic disease (EMA 2009). Multiple phase II trials have evaluated a range of therapies, including immunotherapies and tyrosine kinase inhibitors in this setting; however, treatment responses have generally been limited and no improvements in long-term survival have been demonstrated (Int J Mol Sci. 2022;23:3817). Five-year survival rates for localised disease are 60–70% but there are few treatment options for patients with metastatic disease and, consequently, survival rates are much lower (Discov Oncol. 2025;16:1367). Standard of care continues to revolve around surgery combined with multi-agent cytotoxic chemotherapy, typically methotrexate, cisplatin and doxorubicin, with ifosfamide-based regimens used in selected patients with high-risk or metastatic disease.

Lack of major advances in the treatment of osteosarcoma is partly due to substantial heterogeneity of this tumour type, which remains poorly characterised at the molecular level. As presented at MAP Congress 2026 (London, 10–11 September), a study identified shared cell surface features across 19 patients and 26 primary tumours, suggesting that tumour heterogeneity may not preclude the identification of common therapeutic vulnerabilities (Abstract 6O). These surface markers (ANKH, CLMP, FRMD6, IFITM5, LRRC15, MMP14, MXRA8, PTH1R and RHBDL2) have the potential to be exploited using a range of targeted approaches, including antibody–drug conjugates (ADCs), targeted antibodies, radiopharmaceuticals or engineered cell therapies.

The study also identified a consistent population of osteoclast-lineage immune cells within tumours, including both mononuclear cells and multinucleated giant cells, which may represent precursor populations involved in osteoclast development. These cells could influence the tumour microenvironment and may represent an additional therapeutic target.

These findings add to emerging evidence that transcriptomic profiling may be used to characterise the biological and clinical heterogeneity of osteosarcoma. In 2024, Zheng and colleagues used single cell and spatial transcriptomics in a small patient cohort to identify distinct cellular populations and gene expression profiles associated with tumour biology and treatment response (J Hematol Oncol. 2024;17:71). Similarly, Eigenbrood and colleagues used spatial profiling to identify distinct tumour microenvironments and potential immunosuppressive mechanisms in lung metastases from a small number of paediatric patients with osteosarcoma (Cancer Res. 2025;85:2320–2337). While these studies provide important insights, they are limited by their small sample sizes. In a larger, correlative analysis of the ISG/OS-2 trial, our group at IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy, identified a 21-gene tumour microenvironment signature associated with overall survival, as well as a 31-gene signature associated with overall and event-free survival in patients receiving mifamurtide, highlighting the potential of gene expression profiles for prognostic and treatment response stratification (Clin Cancer Res. 2025;31:3932–3943).

Findings from these translational studies are starting to inform clinical development by identifying novel potential therapeutic targets. In the future, some promise may come from ADC research, which is having an increasing impact on the management of several solid tumours. Of interest, there is an ADC targeting the surface protein B7-H3 that is being evaluated in a phase III trial in China (NCT06935409) and ADCs targeting LRRC15, one of the nine surface markers identified in the spatial atlas (Br J Cancer. 2026; online ahead of print).

Optimistically, there are signs of progress in the field, including the way research is conducted. Clinical trials in osteosarcoma are increasingly including adolescents rather than restricting enrolment to adults, which may reduce the need for separate paediatric phase I studies and potentially accelerate drug development for this underserved population.