Single-Cell Spatial-Temporal Analysis of ZNF451 in Mediating Drug Resistance and CD8⁺ T Cell Dysfunction

Cisplatin is widely used to treat osteosarcoma, but recurrent cases often develop resistance, allowing the disease to progress and complicating clinical management. This study aimed to elucidate the immune microenvironment of osteosarcoma, providing insights into the mechanisms of recurrence and identifying potential therapeutic strategies. By analyzing multiple single-cell and bulk RNA-sequencing datasets, we discovered that the SUMOylation-related gene ZNF451 promotes osteosarcoma recurrence and alters its immune microenvironment. ZNF451 was found to importantly enhance the growth, migration, and invasion of resistant cells while also reducing their sensitivity to cisplatin and lowering their apoptosis rate. Moreover, our data indicated that ZNF451 plays a crucial role in bone resorption and epithelial-mesenchymal transition. ZNF451 also regulates CD8⁺ T cell function, leading to their exhaustion and transition to the CD8T.EXH state. Additionally, β-cryptoxanthin has been identified as a potential therapeutic agent that inhibits osteosarcoma progression by targeting ZNF451. In summary, these findings highlight the critical role of ZNF451 in promoting osteosarcoma progression and underscore its potential as a therapeutic target and biomarker for osteosarcoma.