Multi-omics analysis reveals PITX1 as a predictor of immunotherapy efficacy in clear cell renal cell carcinoma

Abstract Background Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced clear cell renal cell carcinoma (ccRCC), but predictive biomarkers are lacking. The role of paired-like homeodomain 1 (PITX1) in ccRCC remains unclear. Methods Machine learning identified PITX1 as a key biomarker. Multi-omics analyses integrated bulk RNA-seq, single-cell RNA-seq (scRNA-seq), spatial transcriptomics (ST), data from three randomized controlled trials (IMmotion151, CheckMate025, JAVELIN Renal 101) and West China Hospital ccRCC cohort. Results PITX1 was upregulated in ccRCC, associated with BAP1 mutation and hypomethylation. scRNA-seq and ST revealed the expression patterns of PITX1 in different cell clusters. High PITX1 expression correlated with advanced clinicopathological features, poor survival, and metabolic reprogramming towards glucose and methionine metabolism. Enrichment analysis suggested high PITX1 would lead to more malignant tumor biological behaviors. It shaped an immunosuppressive microenvironment with regulatory T cells (Tregs) infiltrated and elevated immune checkpoints. Crucially, high PITX1 indicates inferior benefits for patients receiving immunotherapy. Conclusion PITX1 is a novel biomarker linked to aggressive tumor behavior, metabolic alteration, and immune evasion, predicting poor response to immunotherapy in ccRCC.