Microsatellite instability and PD-L1 expression in sarcomas: current evidence and clinical perspectives

Sarcomas are a diverse group of malignant mesenchymal tumors with complex biology and limited responsiveness to therapies. Several biomarkers yet to be explored as regards sarcoma diagnostics and therapy may be relevant hence the choice of Microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1). Although their expressions are established in various epithelial cancers, their roles in sarcoma remain underexplored. This review provides a comprehensive analysis of the incidence, clinical relevance, and immunotherapeutic implications of MSI and PD-L1 in sarcoma, while also introducing the under-investigated role of lymphovascular invasion (LVI) in modulating immune response. In this study, we found out the rarity but potential therapeutic relevance of MSI-high (MSI-H) status in sarcomas and its correlation with tumor mutational burden (TMB), neoantigen load, and checkpoint blockade sensitivity. Furthermore, this review gave an insight into the immunobiological landscape of sarcomas characterized by concurrent MSI and PD-L1 expression, which, although rare (~ 2-5%), may define a uniquely immunogenic subgroup which may help enable personalized immunotherapy. A key perspective addressed was the interplay between MSI, PD-L1, and LVI which suggested that LVI-positive sarcomas may upregulate PD-L1 as an adaptive immune escape mechanism. Immunohistochemistry, next-generation sequencing data, and recent clinical trials, helped to provide a stratified approach to sarcoma immunotherapy, underscoring the importance of dual biomarker assessment. This review proposes a diagnostic and therapeutic framework that incorporates MSI, IHC, PD-L1, and LVI status to improve prognostication and guide treatment. These novel angles offer fresh direction for future translational research and precision oncology in sarcoma care.