– The immune system is able to defend us against both pathogens and cancer. Starting from this assumption, it is easy to assert that strengthen the immune response against tumor cells may be an incisive strategy of therapy. Several immunotherapy approaches have been proposed over the years; however, all of them have a common characteristic: the ability of T-cytotoxic lymphocytes to attack the tumor. Tumor vaccines are the easier strategy; furthermore, there are few of them available in clinical practice. Adoptive immunotherapy consists instead in the direct administration of a population of tumor specific antigens T-Lymphocytes, which have been firstly selected and then re-arranged in order to attack the tumor. The most promising adoptive immunotherapy strategy is the CAR (chimeric antigen receptors). Direct administration of soluble cytokines has been employed for many years reaching mediocre results, mainly due to the ability of the tumor to bypass the T-cells activation and then the immune response. This happens because the tumor microenvironment has a strong role in modulating immune response, especially through inhibitory cytokines production. A step forward might be to use antibody or small molecules able to interfere with the inhibitory action mediated by the tumor microenvironment. Currently a number of the “so called” checkpoint inhibitors have been experimented in solid tumors as well as most of them have not yet reached the clinic.