As dendritic cells (DCs) are potent at inducing T cell responses, they have been studied for the development of immunotherapies to combat cancer. Several DC surface molecules have been successfully targeted in vivo using monoclonal antibodies to deliver antigen and induce T cell responses that confer tumour protection. One candidate is the C-type lectin-like receptor Clec9A, which shunts antigen efficiently into the cross-presentation pathway, facilitating MHC class I presentation to CD8+ T cells. Recent tumour vaccines utilise tumour-specific mutated peptides, so called tumour neo-antigens. A report identified immunogenic B16 melanoma neo-antigens. By analysis of the immunopeptidome using mass spectrometry, we identified five novel B16 melanoma antigens presented on MHC class I that vary by one amino acid compared to the wild type sequence. Here, we investigated whether these neo-antigens and novel B16 melanoma antigens can be harnessed for vaccinations using Clec9A-targeting antibodies. We demonstrated that the in vivo delivery of these neo- or novel tumour antigens to Clec9A does not induce antigen-specific T cell responses. However, when a pool of these neo- or novel antigens were delivered to Clec9A, significant anti-tumour protection was induced in the B16-metastatic melanoma model. These data suggest that mutant epitopes are poorly immunogenic and that vaccines will require multiple mutant epitopes to induce effective anti-tumour protection. Interestingly, we have also shown that B16 melanoma-bearing mice treated with a CpG adjuvant and checkpoint inhibitors develop a protective T cell-dependent anti-tumour response, yet these protective T cells did not recognise the neo- or novel antigens. These findings highlight that only a small subset of neo-antigens are actively involved in tumour rejection and that these are yet to be identified. From a vaccine perspective, it may become critically important to identify bona fide rejection antigens and delineate these from poorly immunogenic mutant epitopes.