Fig. 4. New antibody-based strategies to target p53 in cancer cells.

a | In the non-proliferative compartment of normal tissues, TP53 is usually silent, and therefore cells do not produce p53 protein and do not present p53-derived peptides on their surface major histocompatibility complex (MHC) class I. b | Proliferating normal cells produce low amounts of p53 protein and present small amounts of p53-derived peptides on their MHC class I (MHC-I). c | In cancer cells expressing wild-type p53 (wtp53), oncogenic stress upregulates p53 mRNA synthesis and translation, causing a more pronounced presentation of p53-derived peptides. These differences in quantity and quality of presented peptides provide the rationale for developing antibody-based strategies to target selectively the cancer cells. T cell receptor (TCR)-like antibodies recognize p53-derived epitopes displayed on MHC-I on the cell surface, triggering an immune response. d | In cancer cells that harbour TP53 missense mutations, p53 protein levels are even more elevated; consequently, such cells may present increased amounts of peptides derived from non-mutated regions of the protein (wtp53 peptides in blue), along with neopeptides comprising the mutated sequence (mutp53 peptide, in red). Bispecific antibodies can be engineered to recognize a neoantigen derived from mutp53 and the TCR–CD3 complex on CD8⁺ T cells, which results in selective cytotoxicity against mutp53-expressing cancer cells.