Dynamic immune state transitions and metastatic niche remodelling drive osteosarcoma evolution as a barrier-restricted immune-cold ecosystem

Abstract

Osteosarcoma exhibits limited responsiveness to immune checkpoint blockade, a feature commonly referred to as immune coldness. However, interpreting immune coldness as a fixed tumour trait may underestimate the spatially and temporally dynamic processes that govern immune resistance. Accumulating evidence instead supports an evolutionary ecosystem view, in which tumour-intrinsic defects in immune recognition, lymphocyte exclusion, myeloid predominance, and metastatic niche formation collectively contribute to clinically non-productive immunity, rather than representing discrete or mutually exclusive stages. Single-cell, spatial, clinical, and translational studies further highlight pronounced heterogeneity among primary, treatment-exposed, and metastatic lesions, with particularly distinct immune architectures observed in pulmonary sites. In this context, lung metastases are not merely endpoints of dissemination, but active immune-modulatory niches in which macrophages, granulocytic myeloid-derived suppressor cells, fibroblasts, and spatially restricted lymphocytes jointly shape therapeutic resistance. These observations motivate a shift away from modality-centred therapeutic escalation toward immune state-guided stratification, sequential reprogramming of the tumour ecosystem, and barrier-specific treatment strategies. Separating clinical evidence from patient-derived, translational, and preclinical findings further provides a framework for prioritizing spatial biomarkers, designing adaptive clinical trials, and developing lung-metastasis-focused immunotherapeutic approaches.