Biomarker‑guided selection of potent tumor‑specific TCRs

Tumor antigen‑specific T cells are central to cancer control and are already exploited in TCR‑engineered T‑cell therapies and TIL products. However, only a fraction of tumor‑reactive TCRs are truly protective. Because the TCR repertoire is highly dynamic across tissues and over time, and functional avidity is difficult to measure, identifying high‑functionality TCRs remains complex, resource‑intensive and a key bottleneck for therapeutic and diagnostic development.

The invention provides a biomarker‑based system to identify highly functional tumor‑specific TCRs directly from peripheral blood. Single‑cell sequencing of neoantigen‑specific T cells combined with CRISPR‑Cas9 TCR reexpression shows that TCRs with superior protective capacity are enriched in T cells with signatures of recent activation. PD‑1 surface expression and defined activation‑gene markers form a practical, scalable framework to enrich, rank and prioritize such TCRs for therapeutic and diagnostic use.