Targeted Therapies and Immunotherapy in Bone and Soft Tissue Sarcomas: Current Evidence and Future Directions

Bone and soft tissue sarcomas represent a heterogeneous group of rare malignancies with diverse molecular profiles and clinical behaviors. Despite advances in surgery and radiotherapy, outcomes for patients with advanced or metastatic disease remain poor, underscoring the need for effective systemic therapies. Over the past two decades, the emergence of targeted therapies and immunotherapy has transformed the therapeutic landscape for selected sarcoma subtypes. Tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib have dramatically improved outcomes in gastrointestinal stromal tumors (GIST), while pazopanib has demonstrated activity across multiple non GIST soft tissue sarcomas. Molecularly defined subsets-including NTRK fusion sarcomas, ALK rearranged inflammatory myofibroblastic tumors, and MDM2 amplified liposarcomas-have benefited from precision guided approaches. Immunotherapy has shown promise in certain sarcoma subtypes, particularly undifferentiated pleomorphic sarcoma (UPS) and alveolar soft part sarcoma (ASPS), where immune checkpoint inhibitors have yielded durable responses. However, most sarcomas remain immunologically "cold," with low tumor mutational burden, sparse T cell infiltration, and an immunosuppressive microenvironment. Combination strategies integrating TKIs, immune checkpoint inhibitors, epigenetic modulators, and radiation therapy are being actively explored to enhance immunogenicity and overcome resistance. This review synthesizes current evidence on targeted therapies and immunotherapy in bone and soft tissue sarcomas, highlights molecular biomarkers of response, and discusses emerging therapeutic strategies.