The Immunological Landscape of the Tumor Microenvironment: Implications for Immunotherapy of Unresectable and Metastatic Soft Tissue Sarcomas

The field of immunotherapy for unresectable soft tissue sarcomas (STS) is transitioning from a one-size-fits-all approach toward a precision immuno-oncology paradigm. The pronounced immunological heterogeneity among histological subtypes and the limited predictive capacity of traditional classification underscore the imperative for immune-based stratification. Approximately 20% of STS exhibit an immune-activated tumor microenvironment, characterized by robust cytotoxic T lymphocyte infiltration, B-cell enrichment, and tertiary lymphoid structures (TLS); these patients demonstrate significantly higher objective response rates to immune checkpoint inhibitors (ICIs) and may be prioritized for such therapy. TLS status could be incorporated into routine clinical decision-making as a robust immunological biomarker for treatment selection. For the majority of patients with TLS-negative, immunologically “cold” tumors, however, single-agent ICIs are insufficient. Combination strategies designed to remodel the immunosuppressive tumor microenvironment represent a promising approach: enhancing tumor immunogenicity through epigenetic modulators, improving antigen presentation via CD47/SIRPα blockade, and exploring dual-checkpoint blockade to overcome T-cell exhaustion. For translocation-associated sarcomas, where neoantigen generation is inherently limited, adoptive cell therapies targeting specific antigens represent a particularly promising avenue. Biomarker-driven basket or umbrella trial designs are paramount to efficiently identifying optimal combination regimens and improving overall survival outcomes for patients with unresectable disease.