New strategy could make p53-mutant cancers visible to immunotherapy

Dana-Farber Cancer Institute research reveals how p53-mutant cancers hide from T cells and proposes an "immunopeptidome shift" strategy to make "cold" tumors visible to immunotherapy, potentially improving treatment for hard-to-treat cancers. The study, published in Immunity, found that many p53 mutations fail to produce stable surface targets for T cells due to poor processing, weak HLA binding, or enzyme-driven destruction. Blocking ERAP1 restored immune recognition in lab experiments, while other mutations produced unstable targets that weakened T-cell responses. The findings caution against assuming predicted mutations are useful immune targets, as processing and stability are critical. The proposed drug-induced antigen display shift could complement existing therapies by exposing multiple new targets, though no clinical drug has yet been tested in patients.