Yeast surface display meets immunotherapy: unlocking the potential of T cells.

Abstract

While T-cell receptors (TCRs) hold immense therapeutic potential, their clinical translation is bottlenecked by the scarcity of high-affinity, specific clones and the instability of recombinant formats. Existing display technologies fall short: phage display often fails to produce properly folded TCRs, and mammalian display is low-throughput. This review is the first to comprehensively synthesize how yeast surface display (YSD) is uniquely positioned to overcome these hurdles and build a new pipeline for TCR based drug discovery. We articulate how YSD's eukaryotic machinery enables the robust expression and engineering of complex TCRs and peptide-MHC (pMHC) libraries. We then critically catalog and evaluate pioneering strategies where YSD has been used to evolve TCRs with enhanced affinity and stability while minimizing cross-reactivity and discover novel antigenic targets through unbiased library-to-library screening. By mapping this largely pre-clinical landscape, our work establishes a foundational framework that bridges fundamental protein engineering with future therapeutic applications. We conclude by outlining a translational roadmap, arguing that YSD derived molecules are poised to become the cornerstone of safer, more effective, and personalized T-cell therapies.