DUET: a graph-based workflow for TCR-epitope prioritization and tumor-reactive T-cell identification.

Accurate prioritization of T-cell receptor (TCR)-epitope interactions and identification of tumor-reactive T cells are important but difficult steps in immunotherapy-oriented bioinformatics workflows. Existing methods typically address these tasks separately and either model TCR-epitope pairs as independent observations or rely primarily on transcriptomic signatures. In this study, we present DUET (Dual Unified Evaluation of TCR-Epitopes and Tumor-reactive T cells), a graph-based computational workflow that unifies both applications within a single heterogeneous graph framework. The protocol represents TCRs, epitopes, and T cells as typed nodes connected by similarity and association edges, and combines pretrained sequence embeddings with edge-aware graph attention, Laplacian positional encoding, and bidirectional cross-domain attention. Applied to the IEDB and VDJdb benchmarks, DUET achieved AUROC/AUPR values of 0.937/0.922 and 0.992/0.990, respectively, outperforming five state-of-the-art algorithms under standard evaluation. On a single-cell RNA-seq tumor-reactivity benchmark, the workflow achieved an area under the receiver operating characteristic curve of 0.985 and an area under the precision-recall curve of 0.975, substantially exceeding transcriptomic signature-based baselines. Additional generalization analyses showed that DUET's clearest graph-specific benefit occurred under epitope-disjoint TCR-epitope prediction. Ablation analysis showed that Laplacian positional encoding provided the largest performance gain, particularly in sparse graph settings. These results suggest that heterogeneous graph modeling can serve as a practical protocol for integrating receptor sequence, antigen context, and cellular phenotype in computational immunology.