A carcinogen-induced mouse tumour model is used here to show that mutant tumour-specific antigens are targets for CD8+ T-cell responses, mediating tumour regression after checkpoint blockade immunotherapy, and that these antigens can be used effectively in therapeutic vaccines; this advance potentially opens the door to personalized cancer vaccines. In many individuals, immunosuppression is mediated by T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), immunomodulatory receptors expressed on T cells. Matthew Gubin et al. use the MCA mouse sarcoma model to show that mutant tumour antigens serve as targets for CD8+ T-cell responses, mediating tumour regression after checkpoint blockade immunotherapy with anti-PD-1 and/or anti-CTLA-4. The authors demonstrate that these antigens can be used effectively in therapeutic vaccines, suggesting a possible route to personalized cancer vaccines. The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity1,2,3,4,5,6, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion1,2,7. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells8,9. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits—including durable responses—to patients with different malignancies10,11,12,13. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.