PSIP1 Orchestrates Immune Escape in Osteosarcoma: Insights From Single‐Cell Analysis and Implications for Immunotherapy Resistance

Background Osteosarcoma (OS) is characterized by a highly heterogeneous tumor microenvironment (TME) that frequently limits the efficacy of immunotherapy. Identifying molecular drivers of immune escape (IE) is essential for improving therapeutic outcomes. Methods We integrated single‐cell RNA sequencing (scRNA‐seq) and bulk transcriptomic data to dissect the OS immune landscape. Utilizing high‐dimensional weighted gene coexpression network analysis (hdWGCNA), we identified gene modules specifically associated with IE. Results Within the IE‐related module, PSIP1 emerged as the most significant prognostic hub gene. ScRNA‐seq analysis localized PSIP1 primarily to malignant cell populations. High PSIP1 expression consistently correlated with abbreviated overall survival across multiple independent cohorts. Functional enrichment and GSEA revealed that PSIP1 is intrinsically linked to the suppression of critical immune effectors, including B‐cell signaling, lymphocyte chemotaxis, and NK cell–mediated cytotoxicity. Crucially, PSIP1 exhibited robust predictive performance for immunotherapy response; elevated PSIP1 levels were associated with diminished activity of multiple established immune‐response signatures and poor survival in patients undergoing checkpoint blockade. Conclusion Our study positions PSIP1 as a novel orchestrator of immune evasion and a promising predictive biomarker for immunotherapy resistance in OS, offering a potential target to overcome therapeutic recalcitrance.