CAF-mediated immune exclusion in osteosarcoma: mechanisms, translational vulnerabilities, and therapeutic strategies

Abstract

Osteosarcoma remains a highly aggressive bone malignancy with limited therapeutic progress in metastatic and treatment-refractory disease. Beyond tumor-intrinsic drivers, the tumor microenvironment has emerged as a critical determinant of immune escape, therapeutic resistance, and poor clinical outcome. Among stromal components, cancer-associated fibroblasts (CAFs) are increasingly recognized as central regulators of extracellular matrix remodeling, immune suppression, and treatment failure; however, their specific translational relevance in osteosarcoma remains incompletely defined. In this review, we synthesize current evidence on CAF-mediated immune exclusion, immune suppression, and therapy resistance in osteosarcoma and organize the field into an evidence-stratified translational framework. We discuss how CAFs shape a treatment-refractory microenvironment through matrix deposition and stiffening, cytokine and chemokine signaling, exosome-mediated communication, and metabolic competition, while emphasizing the distinct stromal contexts of primary osteosarcoma and pulmonary metastases. We further summarize emerging CAF states and stromal-immune interaction programs identified by single-cell and spatial profiling, with emphasis on their implications for T-cell exclusion, myeloid reprogramming, chemotherapy resistance and immunotherapy response. Therapeutically, we evaluate CAF normalization, matrix-targeted intervention, local delivery strategies, and rational combination approaches, highlighting NADPH oxidase 4 inhibition, focal adhesion kinase-related stromal targeting and sequence-based chemoimmunotherapy as key translational directions that require further validation through delivery feasibility, safety assessment, and biomarker-guided patient stratification. Current evidence supports CAF-directed intervention in osteosarcoma primarily as a microenvironment-modulating and treatment-sensitizing strategy rather than as a stand-alone cytotoxic approach. Clinical translation will require osteosarcoma-specific validation in bone-relevant and immunocompetent models, multiplex CAF biomarker panels compatible with formalin-fixed, paraffin-embedded tissue, and rational treatment-sequencing strategies that integrate stromal normalization with chemotherapy, surgery, and immunotherapy.