TCRdesign: an antigen-specific generative language model for de novo design of T-cell receptors.

T-cell receptors (TCR), which are heterodimers of $\alpha $ and $\beta $ chains that recognize foreign antigens, are of great significance to current immunotherapy. Although artificial intelligence (AI) has explosively accelerated de novo protein design, the challenge of therapeutic TCR design has been overlooked by most researchers. Existing TCR engineering relies heavily on isolating antigen-specific TCRs from tumor tissues, which requires a large amount of labor resources and wet experimental verification. To mitigate this issue, we present TCRdesign, a pretrained generative protein language model (PLM) for the de novo design of artificial TCR $\beta $-chain complementarity-determining region 3 sequences conditioned on antigen-binding specificity (BS). In parallel, we develop a high-accuracy binding predictor (TCRBinder) that couples paired $\alpha $/$\beta $ chain information with antigen sequences to assess BS. Our in silico comparisons demonstrate that (i) TCRdesign surpasses state-of-the-art baselines in generating antigen-specific TCR sequences. The model leverages paired-chain coherence to refine amino-acid level interaction patterns. (ii) TCRdesign-generated TCR sequences exhibit better antigen binding capability to diverse oncogenic hotspots compared with natural counterparts. (iii) TCRdesign inherits the intrinsic properties of large PLMs, enabling effectively identify the determinant residues in TCR-antigen binding, which enhances its interpretability. These results highlight the significant capability of TCRdesign in understanding and generating TCR sequences with an antigen-specific interaction pattern, charting a versatile path toward AI-driven T-cell engineering for precision immunotherapy.

© The Author(s) 2025. Published by Oxford University Press.