Inferring translational efficiency from transcriptomes improves noncanonical neoantigen prioritization and cancer...

Accurate assessment of protein translation is crucial for understanding disease variant functions, but mRNA-protein discrepancy limits transcriptomics-based clinical oncology. While ribosome profiling directly measures translation, its clinical application is constrained by cost and complexity. Deep learning models like Translatomer infer translation efficiency from RNA-seq, but whether in silico translatomes provide superior clinical utility over standard RNA-seq remains unexplored. Here, we present a multidimensional framework evaluating the translational inference strategy across 15 independent datasets. Inferred translational profiles outperform conventional RNA-seq proxies in recapitulating ribosome occupancy and uncover the "dark proteome" through lncRNA translational potential prediction. We integrate this strategy into a translation-aware neoantigen pipeline, identifying high-confidence noncanonical neoantigens neglected by expression-based filtering. Applying this framework to glioma stratification reveals distinct subtypes and corrects high-risk patient misclassification by expression-based methods, as validated by survival analysis. Our study establishes translational inference as a cost-effective enhancement for precision oncology, refining patient stratification and expanding immunotherapeutic targets.