Immunotherapy in Soft Tissue Sarcomas—An Ongoing Quest

Soft tissue sarcomas (STSs) are rare and heterogeneous mesenchymal malignancies characterized by diverse molecular profiles and immune landscapes. Although immunotherapy has revolutionized the treatment of specific solid tumors, its efficacy in STSs remains limited and variable across histotypes. This review explores the panorama of biomarkers of immunotherapy sensitiveness in STSs, with particular emphasis on tumor-intrinsic features and on tumor microenvironment (TME) signatures. Current evidence highlights low tumor mutational burden, rare microsatellite instability, heterogeneous antigen expression, and epigenetic suppression of antigen presentation as hallmarks of the immune resistance that is characteristic of many STSs. However, growing evidence underlines TME composition as a major determinant of response to different types of immunotherapy. Indeed, the presence of B-cell-rich tertiary lymphoid structures and certain traits of adaptive immune responses are provenly associated with enhanced sensitivity to immunotherapy and enhanced outcomes. We further discuss emerging strategies aimed at enhancing STS immunogenicity, either by increasing intrinsic tumor immunogenicity or remodeling TME composition and functional profile. Collectively, the available data support a paradigm shift from a sarcoma cell-centered approach toward a multi-compartment TME-including strategy, providing a framework for the development of more effective and personalized immunotherapeutic strategies in STS.