Over the past decade, significant advances in immunotherapy, such as already approved by regulatory agencies several immune checkpoint blockade (ICB) or inhibitor (ICI) molecules and adoptive cellular therapy (ACT), including chimeric antigen receptor T-cell (CAR T-cell) therapy and tumor-infiltrating lymphocyte (TIL) therapy, have revolutionized the treatment of many cancer types (Blass and Ott, 2021; Lahiri et al., 2023; Oliveira and Wu, 2023; Puig-Saus, et al., 2023). At the same time, the field of vaccine therapy, another component of cancer immunotherapy, despite decades-long intense efforts, is still transmitting signals of promises and awaiting strong data on efficacy to proceed with regulatory approval (Biswas et al., 2023; D'Alise et al., 2023; Debien et al., 2023; Liu et al., 2023). The capacity of the immune system to prevent the development of cancer or eliminate tumor cells stems from the cancer immunoediting hypothesis, which is also behind the basics for the development of cancer vaccines (Schreiber et al., 2011; Desai et al., 2022). The renewed interest in cancer vaccines is due to the data showing that the preferred targets of the above-mentioned therapeutic interventions are mutated/modified forms of wild-type antigens, known as neoantigens, with the putative capacity to evade immune tolerance mechanisms (Hu et al., 2021; Holm et al., 2022; Lybaert et al., 2023a). The field of cancer vaccines faces standard challenges, such as tumor-induced immunosuppression, immune response in inhibitory tumor microenvironment (TME), intratumor heterogeneity (ITH), permanently evolving cancer mutational landscape leading to neoantigens, and less known obstacles: neoantigen gain/loss upon immunotherapy, the timing and speed of appearance of neoantigens and responding T cell clonotypes and possible involvement of immune interference/heterologous immunity, known from studies on viruses as original antigenic sin (OAS), in the complex interplay between evolving tumor epitopes and the immune system (Burnett et al., 2018; Waldman et al., 2020; Hwang et al., 2022; Lowery et al., 2022; Ho et al., 2023; Niknafs et al., 2023; Schiepers et al., 2023). We are convinced that any objective questioning of the feasibility and future of neoantigen cancer vaccines may help to search for alternative approaches and make more rational decisions (Finn and Rammensee, 2018; Kissick, 2018; Manoutcharian et al., 2021). It is worth mentioning that in the field of prophylactic cancer vaccines, the massive application of vaccines against the human papillomavirus (HPV) and hepatitis B virus (HBV) has significantly reduced cancer cases.