Application of CAR-T cell therapy in orthopedics: From bone malignancies to non-malignant musculoskeletal disorders

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed hematologic oncology, but its application in orthopaedic diseases remains at an early stage. In bone malignancies, including osteosarcoma, chondrosarcoma, Ewing sarcoma, and bone metastases, antigen heterogeneity, limited trafficking and persistence, and the immunosuppressive skeletal microenvironment restrict efficacy. CAR-engineered approaches are also emerging in non-malignant disorders: CD19-directed CAR-T therapy has shown early clinical activity in refractory rheumatoid arthritis and other autoimmune rheumatic diseases, whereas senolytic CAR-T strategies for osteoarthritis remain preclinical. This review summarizes current evidence across malignant and non-malignant orthopaedic conditions, with emphasis on target selection, safety, and translational feasibility. Key barriers include antigen escape, impaired infiltration, limited persistence, local immunosuppression, manufacturing complexity, and on-target/off-tumour toxicity. Emerging strategies include multi-target receptors, chemokine receptor engineering, locoregional delivery, safety-control systems, and allogeneic or point-of-care manufacturing. Current evidence supports CAR-T and related CAR-engineered cells as potential complementary approaches for selected refractory orthopaedic conditions, although further translation requires stronger clinical evidence and improved biological and manufacturing strategies. The Translational Potential of this Article: This review identifies disease-specific targets, barriers, and engineering priorities relevant to translating CAR-engineered cell therapies into orthopaedic practice. These considerations may inform preclinical validation and early-phase trials in refractory bone malignancies and selected non-malignant musculoskeletal disorders.