Single-cell mitophagy patterns dictate intercellular crosstalk in the tumor microenvironment to promote osteosarcoma progression.
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BACKGROUND: Osteosarcoma (OS) is a highly aggressive primary bone malignancy in adolescents, with poor prognosis due to limited diagnostic and therapeutic strategies. Mitochondrial dysfunction is a hallmark of cancer, and mitophagy, the selective clearance of damaged mitochondria, critically maintains cellular homeostasis. However, the specific role of mitophagy in shaping the OS tumor microenvironment (TME) at single-cell resolution remains poorly understood. This study aims to systematically characterize mitophagy patterns within the OS TME and investigate their impact on intercellular communication, tumor progression, and patient prognosis. METHODS: We analyzed single-cell RNA sequencing data from OS samples using non-negative matrix factorization to cluster cells based on mitophagy-related genes. We characterized distinct mitophagy-associated subtypes of TME cells. Pseudotime trajectory, cell-cell communication), gene regulatory network, and functional enrichment analyses were performed. Prognostic significance was evaluated using GSVA and Cox regression in bulk RNA-seq cohort. Immunotherapy response was predicted using the TIDE algorithm. RESULTS: We identified diverse mitophagy-activated cellular subtypes within the TME. Mitophagy-active CAFs and macrophages exhibited enhanced angiogenic signaling to endothelial cells. Mitophagy-associated CD8+ T cells displayed marked exhaustion features, while macrophages showed metabolic reprogramming. Clinically, higher infiltration of these mitophagy-related subtypes was consistently associated with poorer overall survival. TIDE analysis indicated that mitophagy patterns potentially correlate with immune checkpoint blockade response. CONCLUSIONS: Our findings reveal that mitophagy drives complex intercellular crosstalk in the OS TME, promoting angiogenesis and immunosuppression. Mitophagy-related signatures serve as robust prognostic biomarkers. These insights suggest that targeted inhibition of mitophagy, rather than activation, represents a promising therapeutic strategy, providing a novel framework for improving OS patient outcomes.