Engineered Catch Bonds Overcome T-Cell Tolerance in Cancer Therapy

Overcoming central tolerance to tumor-associated self-antigens remains a major barrier to effective TCR-T cell therapies for solid tumors, particularly when physiologic TCR affinity must be maintained to preserve specificity. Chen, Mao, and colleagues describe a biophysically driven TCR “turbocharging” strategy that enhances antitumor potency without affinity maturation by engineering force-dependent catch bonds into an otherwise weak, naturally occurring prostatic acid phosphatase (PAP)-specific TCR. Using a structure-agnostic, three-step positional scanning and mutagenesis pipeline, the authors identified catch-bond hotspots within CDR1α of a PAP22/HLA-A*02:01–restricted TCR. Single or paired substitutions at residues S30 and S32 increased TCR–pMHC bond lifetimes under force, as measured by biomembrane force probe assays, while preserving low micromolar binding affinities. Enhanced bond lifetimes correlated more strongly with T-cell activation, cytotoxicity, proliferation, and resistance to exhaustion than conventional three-dimensional affinity metrics. Two engineered variants, S32Mα and S30E32Qα, displayed markedly improved tumor killing across multiple in vitro assays and achieved durable tumor control in immunocompromised xenograft models. High-resolution crystal structures demonstrated that catch-bond engineering introduced minimal perturbation to overall TCR–pMHC geometry. Molecular dynamic simulations revealed that the S32M substitution reorganized water-mediated interactions to prime transient peptide contacts during force application, providing a mechanistic explanation for enhanced signaling. Extensive yeast-display pMHC library screening confirmed that catch-bond–engineered TCRs did not exhibit increased off-target cross-reactivity and, in some cases, showed improved specificity for the cognate PAP epitope. Collectively, these findings establish catch-bond engineering as a generalizable strategy to overcome T-cell tolerance by selectively amplifying mechanotransductive signaling rather than affinity, offering a safer path to potent TCR-T cell therapies that target nonmutated tumor-associated antigens.Chen X, Mao Z, Kolawole EM, Persechino M, Jude KM, Ogishi M, et al. Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering. Science 2026;391:eadx3162.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.