{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:20:39Z","timestamp":1789510839088,"version":"build-2803163510"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T00:00:00Z","timestamp":1752624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Osteosarcoma (OS) is the most common primary malignant bone tumour of childhood, yet five-year survival has plateaued at ~60\u201370% for localised disease and plunges below 30% once metastasis emerges. Formerly viewed as a cell-intrinsic neoplasm entombed in mineralised bone, OS is now understood as a spatially stratified ecosystem whose immune-evasion niches choreograph progression. Three-dimensional spatial transcriptomics (3-D ST) fuses barcode-based transcript capture with volumetric reconstruction, preserving x-, y- and z-axis context and exposing concentric C1QC necrotic belts, MCAM (melanoma cell-adhesion molecule, CD146) peri-vascular corridors, hypoxic glycolytic rims and therapy-induced tertiary-lymphoid islets that collectively sequester cytotoxic lymphocytes. Pre-clinical atlases link PD-L1 high SOX9 stem-like cells, LGALS3 macrophages and VEGFA-driven endothelial tips to chemoresistance and immune-checkpoint failure, while ligand\u2013receptor inference highlights VEGFA\u2013VEGFR2, CXCL12\u2013CXCR4 and complement\u2013CSF1R axes as actionable bottlenecks. Translational efforts already echo these insights: dual MCAM\/VEGFR blockade collapses vascular gates, C1s or CSF1R antagonists dismantle necrotic-core \u201ccold pockets\u201d, and MCT1\u2013POSTN combinations target lactate-stiffened stromal shells. By weaving methodological advances with emergent biology, this review crystallises how 3-D ST redefines OS immunopathology, sharpens biomarker discovery and accelerates spatially guided combination therapies. We aim to expose diagnostic blind spots, spotlight niche-directed interventions and chart a roadmap toward lifting the long-standing therapeutic ceiling in osteosarcoma.<\/jats:p>","DOI":"10.3389\/fonc.2025.1640645","type":"journal-article","created":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T04:12:21Z","timestamp":1752639141000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Deciphering spatially confined immune evasion niches in osteosarcoma with 3-D spatial transcriptomics: a literature 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