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. Tumour vaccines often utilise tumour-associated peptides, and more recently, tumour-specific mutated peptides, so called tumour neo-antigens. A recent report identified immunogenic B16 melanoma neo-antigens. Here, we investigated whether these tumour antigens can be harnessed for vaccinations using Clec9A-targeting antibodies. We demonstrated that the in vivo delivery of these neo-antigens to Clec9A does not induce antigen-specific T cell responses that can be detected by ELISpot. However, vaccination with some of these neo-antigens did induce cytotoxic T lymphocytes that killed peptide-coated target cells in vivo. Furthermore, when a pool of these neo-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 new adjuvant and checkpoint inhibitors develop a protective T cell-dependent anti-tumour response, yet these protective T cells did not recognise the described neo-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. In that vein, we have recently discovered spliced antigens that may prove to be more immunogenic.