Spatial Profiling Identifies Regionally Distinct Microenvironments and Targetable Immunosuppressive Mechanisms in Pediatric Osteosarcoma Pulmonary Metastases

Osteosarcoma is the most common malignant bone tumor in young patients and remains a significant clinical challenge, particularly at the metastatic stage. Studies detailing the immunosuppressive mechanisms within the metastatic osteosarcoma microenvironment are needed to elucidate the cellular communities in the metastatic microenvironment that support metastatic growth and to identify therapeutic approaches to target the cross-talk between cancer cells and their microenvironment. In this study, we performed spatial transcriptional profiling on a cohort of osteosarcoma pulmonary metastases from pediatric patients. The data revealed a conserved spatial gene expression pattern resembling a foreign body granuloma, characterized by peripheral inflammatory signaling, fibrocollagenous encapsulation, lymphocyte exclusion, and peritumoral macrophage accumulation. The intratumoral microenvironment of these lesions, however, lacked inflammatory signaling. Exploration of spatially distinct drug-gene interactions identified the CXCR4 signaling axis, which displayed spatial heterogeneity and complexity, as a potential therapeutic target that bridges both the intra- and extratumoral microenvironments. Collectively, this study reveals that metastatic osteosarcoma comprises multiple regionally distinct immunosuppressive microenvironments. SIGNIFICANCE: Exploration of spatially resolved microenvironments in metastatic osteosarcoma tissues reveals how the tissue architecture promotes immunosuppression and identifies actionable processes to enhance immunotherapy efficacy.