Decoding the role of SLC25A5 in osteosarcoma drug resistance and CD8+ T cell exhaustion: The therapeutic potential of phyllanthin.

Osteosarcoma is an aggressive malignant bone tumor with an obscure etiology, as well as high prevalence and poor prognosis in children and adolescents. We aimed to investigate the pathogenesis of osteosarcoma through a comprehensive analysis of the tumor immune microenvironment (TIME) using multiple single-cell RNA sequencing datasets. SLC25A5, a gene implicated in cellular aging, significantly influenced osteosarcoma development by altering the TIME and promoting CD8+ T cell exhaustion, which contributed to reduced chemosensitivity. Experimental validation demonstrated that SLC25A5 enhanced the proliferative, migratory, invasive, and osteolytic properties of drug-resistant osteosarcoma cells while reducing apoptosis, intensifying cisplatin resistance. Phyllanthin inhibited the malignant phenotype of cisplatin-resistant osteosarcoma cells and enhanced their sensitivity to cisplatin by suppressing SLC25A5 expression. This study highlights a novel pathogenic role of SLC25A5 in osteosarcoma and presents Phyllanthin as a promising therapeutic agent. Our study offers a pioneering exploration of the single-cell spatiotemporal evolution of osteosarcoma and identifies SLC25A5 as a critical factor in drug resistance and immune evasion. By integrating advanced single-cell technologies and functional assays, we provided novel insights into the molecular mechanisms underlying osteosarcoma progression and treatment resistance, facilitating innovative therapeutic strategies.