**1. Introduction**

Cancer is one of the three leading causes of death in industrialized countries, along with infectious and cardiovascular diseases. It is caused by the abnormal growth of the progeny of transformed cells, which have previously been subjected to mutations and several other alterations in the cell cycle and metabolism that contributed to giving these cells the typical tumor-like phenotype [1]. One of the most critical aspects in the fight against cancer is the tumor's ability to spread in the patient's body, even in locations far from the primary tumor location, developing metastasis [1]. This event could make the clinical picture significantly more complicated, since in order to cure cancer, all malignant cells in the patient's body need to be destroyed and removed, preferably without side effects for the patients [2].

The immune system (IS) is a complex system which is responsible for the protection of the human body. It consists of many cell types, structures and chemical mediators with different functions that can regulate each other to work effectively and neutralize components recognized as non-self. The idea that our immune system could act as a weapon or a prevention tool against cancer cells has always been particularly attractive, especially because of the specificity of the immune response that could be elicited. The first clue about the host immune system's alleged protective role against cancer emerged from a series of experiments on mice [3], in which it was noticed that mice previously immunized with irradiated tumor cells that were then challenged with an injection of tumor viable cells showed protection against the tumor. The same response was not observed in T cell deficient mice or mice which had been challenged with viable cells from a different tumor than the one used for the immunization process [3]. This evidence led to the discovery of the host immune system involvement in tumor-disruption and tumor prevention mechanisms, suggesting what many years of research have now shown, that is, that the host immune system has a role in the prevention and rejection of tumors [4]. However, since neither the immune system nor the tumor could be defined as simple networks, the relationship between them is obviously complex. This is due to the several factors which are involved in determining the evolution of tumorigenesis, among which there is also the immune system, which can surely exert an anti-tumor effect, but with specific subsets of immune cells, it may also perform a "foster" action on the tumor [5,6]. There are many ways that the IS could carry out its anti-tumor action. First, it protects the host from virus-induced tumors by eliminating or suppressing viral infection [7]; second, it promptly resolves inflammations, avoiding tissue exposure to an inflammatory environment, which is conducive to tumorigenesis [7,8]; third, the immune system is capable of specific recognition and disruption of tumor cells on the basis of their expression of molecules which work as antigens [7,9]. This last specific feature of IS is also known as immunosurveillance, and it is extremely important to guarantee a specific immune reaction which is directed only to tumor cells, sparing healthy tissue and avoiding many side effects [10]. This is possible because tumor cells are antigenic, meaning they express specific antigens usually called tumor associated antigens (TAAs), tumor specific antigens (TSA) or tumor rejection antigens (TRAs) [11–13]. The recognition and identification of these antigens is now a fundamental part in the development of effective immunotherapy, since they represent the main component with which T cells can recognize tumor cells to be activated and trigger the specific immune response. Most of the early efforts in antigens identification focused on shared tumor antigens, which could represent a valid alternative for a wide range of cancers, but these antigens are also expressed in a variety of self-tissues, leading to immunologic tolerance [14,15].

Therefore, the focus of research has slowly shifted to more tumor-specific antigens, usually generated from point mutations in normal genes, known as "neoantigens" [16,17]. Despite advances in conventional cancer therapies including chemotherapy, immuno-oncology is becoming more popular and effective in various cancer indications, including melanoma. Therefore, more conventional modalities seem to be gradually being replaced by more effective IO agents and their combinations (Table 1).


**Table 1.** The combinatory therapy of oncolytic vectors and CPIs for melanoma treatment.
