Tumour immune ecosystem in bone tumours: resolving the bone-tumour paradox from spatial architecture to systemic remodelling

Malignant bone tumours, encompassing osteosarcoma, Ewing sarcoma, and bone metastases secondary to solid tumours, remain among the malignancies with the poorest clinical prognoses. Although immune checkpoint inhibitors have significantly altered the therapeutic landscape across multiple solid tumours, objective response rates in bone tumours have consistently remained extremely low. This striking discordance—wherein the physiologically immune-rich bone marrow niche manifests as a pathological “cold tumour” phenotype—defines the “bone tumour paradox” and highlights the inherent limitations of conventional tumour microenvironment theory in the bone-specific context. Drawing on recent advances in spatial multi-omics, mechanobiology, and immunology, this review proposes the Tumour Immune Ecosystem (TIE) framework, which conceptualises the bone-tumour microenvironment as a highly self-organising, evolutionarily resilient pathological ecosystem. It delineates the spatial architecture comprising the Mechanical Impedance Zone (MIZ) and Immune Exclusion Zone (IEZ), dissects the fivefold defensive barriers—physical impedance, recognition decoupling, niche occupancy, metabolic constraints, and molecular locking—and their non-linear coupling mechanisms that sustain systemic immune resistance. Building upon this framework, the review proposes the Ablation–Normalisation–Priming (ANP) three-stage sequential ecosystem remodelling strategy as a conceptual, hypothesis-driven pathway to systematically dismantle these multidimensional barriers. The TIE framework and ANP strategy provide a novel integrative perspective for resolving the bone-tumour paradox, offering critical insights into cold-tumour microenvironments and embodying a paradigm shift from component-based interventions toward multidimensional systemic ecosystem governance in bone tumour immunotherapy. As a conceptual strategy synthesising primarily preclinical and non-bone-tumour-specific evidence, further experimental and clinical validation will be required.