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Developing broadly applicable neoantigen-directed adoptive cell therapies (ACTs) is challenging because each cancer patient has an unique neoantigen repertoire. Here, the authors present the crystal structures of tumor-specific T cell receptors (TCRs) that recognize a shared neoepitope arising from the R175H driver mutation in the p53 oncogene (p53R175H) alone and bound to p53R175H–HLA-A2, which are of interest for the structure-guided design of TCRs to improve T cell potency for ACT.