CDS1 in Pan-Cancer: A Systematic Multidimensional Evaluation.

INTRODUCTION/OBJECTIVE: CDS1 is a phospholipid-metabolism enzyme with potential value as a biomarker for immune checkpoint blockade response across cancers. We evaluated the pan-cancer prognostic, immune, and functional significance of CDS1 in tumor progression and immunotherapy stratification. METHODS: We integrated multi-omics data from TCGA, GTEx, and cBioPortal across more than 10,000 samples to assess CDS1 expression, survival outcomes, immune correlations, genomic alterations, and immune checkpoint blockade responses. Functional validation was performed in cervical squamous cell carcinoma (CESC) using HeLa and SiHa cells after CDS1 overexpression. RESULTS: High CDS1 expression was associated with favorable outcomes in PD-L1-targeted therapy, including atezolizumab (HR 0.62), and showed similar benefit across nivolumab (HR 0.65) and pembrolizumab (HR 0.71) in seven clinical cohorts totaling 2,847 patients. CDS1 explained 42% of response variance, outperforming tumor mutation burden (28%). In contrast, high CDS1 was associated with resistance to CTLA-4 therapy, including ipilimumab (HR 1.28, p = 0.03). CDS1 correlated with CD8+ T-cell infiltration (r = 0.64), CXCL9/CXCL10 expression (r = 0.52- 0.67), and TNFRSF9 (r = 0.42). In CESC, CDS1 was top-ranked by stage/grade correlation (r = 0.71), and its overexpression induced a 4.8-fold increase in invasion (p < 0.0001). DISCUSSION: These findings suggest that CDS1 links phospholipid metabolism to immune regulation, membrane remodeling, and tumor aggressiveness. Its associations with immune infiltration and differential checkpoint response indicate that CDS1 may help explain immunotherapy outcomes across cancer types. CONCLUSION: CDS1 emerges as a phospholipid-based biomarker for identifying patients likely to benefit from PD-L1 therapy while predicting CTLA-4 resistance.