Spatial ligand–receptor circuits in osteosarcoma: immune resistance in bone and lung niches

Abstract

Osteosarcoma (OS) has shown limited sensitivity to single-agent immune checkpoint blockade. The distribution of immune cells within bone tumors and pulmonary metastases suggests that defective tumor-cell recognition, restricted tissue access and local suppression may contribute to this resistance. This mini-review examines ligand–receptor communication between malignant cells, myeloid cells, fibroblasts and vascular or bone-associated compartments, with attention to the anatomical and experimental settings in which each interaction was studied. Human tissue profiling identifies distinct tumor interiors, myeloid-rich interfaces and fibrocollagenous boundaries, whereas perturbation studies test selected mechanisms within these compartments. GD2-dependent suppression of macrophage phagocytosis involves human SIGLEC7 or murine Siglec-E and downstream SHP2 signaling. CXCL14–integrin α11β1 signaling links OS cells to fibroblast activation and pulmonary niche formation. A separate metabolic circuit couples oxidized-lipoprotein uptake by CD36-positive fibroblasts to ANGPTL4 secretion and integrin α5β1-dependent CD8 T-cell dysfunction. CD24 and macrophage migration inhibitory factor also have OS-specific functional support, although the receptor dependencies inferred from transcriptomic data require more precise attribution. Bone-remodeling and vascular pathways are considered microenvironmental barriers rather than interchangeable immune checkpoints. We distinguish human spatial observations from cell-culture experiments, engineered bone models and animal studies, and separate experimental immune effects from clinical antitumor activity. We also consider how cell-to-tumor distances, compartment-specific receptor expression and stromal architecture could inform biomarker development. These measurements remain candidates for prospective testing rather than established criteria for treatment selection. Linking tissue localization to receptor engagement and immune function offers a route to testing which circuits sustain disease in bone.