Revisiting the Immune Frontier in Soft Tissue Sarcomas

Soft tissue sarcomas (STS) comprise a heterogeneous group of mesenchymal malignancies with limited treatment options and poor outcomes in the advanced setting. Although immune checkpoint inhibitors have transformed the management of many solid tumors, their efficacy in STS has been modest and strongly histology dependent. This review aims to synthesize recent advances in immuno-oncology as applied to STS and to highlight emerging strategies that may overcome resistance and improve patient outcomes.

Thus far, clinically meaningful activity of immune checkpoint inhibitors has been identified select STS subtypes, including undifferentiated pleomorphic sarcoma, angiosarcoma, and alveolar soft part sarcoma. Combination approaches incorporating immune checkpoint inhibitors with chemotherapy, radiation, tyrosine kinase inhibitors, or novel immune modulators have shown enhanced antitumor activity in early-phase and randomized trials. In parallel, engineered T-cell therapies targeting cancer-testis antigens have emerged as a standard-of-care option in synovial sarcoma and are being expanded to other histologies. Finally, advances in tumor microenvironment characterization, including the role of tertiary lymphoid structures and myeloid modulation, are refining patient selection and informing rational trial design. Immunotherapy continues to reshape the therapeutic landscape of soft tissue sarcoma. While immune checkpoint blockade alone benefits only a subset of patients, rational combination strategies and cellular therapies offer promising avenues to broaden clinical efficacy. Continued integration of biomarker-driven approaches, translational correlative studies, and histology-specific trial designs will be essential to fully realize the potential of immunotherapy in STS.