Purpose of Review This review presents a selection of regulatory molecules of tumor microenvironmental properties and metastasis. Signaling pathways controlling mesenchymal biology in bone and soft-tissue sarcomas found in children and adolescents are prioritized. Recent Findings The tumor microenvironment of pediatric tumors is still relatively unexplored. Highlighted findings are mainly on deregulated genes associated with cell adhesion, migration, and tumor cell dissemination. How these processes are involved in a mesenchymal phenotype and metastasis is further discussed in relation to the epithelial to mesenchymal transition (EMT) in epithelial tumors. Cell plasticity is emerging as a concept with impact on tumor behavior. Summary Sarcomas belong to a heterogeneous group of tumors where local recurrence and tumor spread pose major challenges despite intense multimodal treatments. Molecular pathways involved in the metastatic process are currently being characterized, and tumor-regulatory properties of structural components, and infiltrating, non-malignant cell types should be further investigated.

Checkpoint inhibitors are slowly being introduced in the care of specific sarcoma subtypes such as undifferentiated pleomorphic sarcoma, alveolar soft part sarcoma, and angiosarcoma even though formal indication is lacking. Proper biomarkers to unravel potential immune reactivity in the tumor microenvironment are therefore expected to be highly warranted. In this study, intratumoral spatial cross presentation was investigated as a novel concept where immune cell composition in the tumor microenvironment was suggested to act as a proxy for immune surveillance. Double immunohistochemistry revealed a prognostic role of direct spatial interactions between CD11c+ antigen-presenting cells (APCs) and CD8+ cells in contrast to each marker alone in a soft tissue sarcoma (STS) cohort of 177 patients from the Karolinska University Hospital (MFS p = 0.048, OS p = 0.025). The survival benefit was verified in multivariable analysis (MFS p = 0.012, OS p = 0.004). Transcriptomics performed in the TCGA sarcoma cohort confirmed the prognostic value of combining CD11c with CD8 (259 patients, p = 0.005), irrespective of FOXP3 levels and in a CD274 (PD-LI)-rich tumor microenvironment. Altogether, this study presents a histopathological approach to link immune surveillance and patient survival in STS. Notably, spatial cross presentation as a prognostic marker is distinct from therapy response-predictive biomarkers such as immune checkpoint molecules of the PD-L1/PD1 pathway.