Pan-cancer analysis identifies ODF2 as a dual prognostic and predictive biomarker for immunotherapy

Background Transforming immunologically "cold" tumors into inflamed "hot" remains a primary hurdle in cancer immunotherapy. Cancer-testis antigens (CTAs) represent highly promising targets for next-generation therapeutic cancer vaccines and adoptive cell therapies. However, the systemic immunogenomic landscape and prognostic significance of Outer Dense Fiber 2 (ODF2), an emerging CTA, across human malignancies remain largely unexplored. This study comprehensively decodes the pan-cancer immunological and prognostic characteristics of ODF2 to evaluate its broad-spectrum clinical utility.Methods Multi-omics and clinical data from the TCGA, GTEx, and HPA databases were analyzed to assess the prognostic value of ODF2. Gene Set Enrichment Analysis (GSEA) was performed to identify associated biological pathways. The correlation between ODF2 expression, immune cell infiltration, and immune checkpoints was evaluated using multiple deconvolution algorithms. The predictive value of ODF2 for immune checkpoint blockade (ICB) therapy was assessed using independent clinical cohorts from the BEST database.Results ODF2 is significantly upregulated across multiple solid tumors and correlates with poor clinical outcomes. GSEA revealed that high ODF2 expression is strongly enriched in cell cycle and oncogenic pathways. Furthermore, ODF2 expression exhibits positive correlation with immunosuppressive cell populations and major inhibitory immune checkpoints, while inversely correlating with infiltrating CD8+ T cells. ROC analyses demonstrated that ODF2 expression reliably predicts clinical responsiveness to anti-PD-1 and anti-CTLA-4 therapies in diverse clinical cohorts.Conclusions ODF2 is strongly associated with an immunosuppressive TME and serves as a predictive biomarker for ICB efficacy. Rather than definitively validating it as a universal target, these findings provide a theoretical rationale for investigating ODF2 as a potential candidate for next-generation peptide vaccines and adoptive T-cell therapies to overcome ICB resistance.