The development of increased knowledge of the interaction between cancer cells, immune cells, and the tumor microenvironment is of special interest because immune and niche-related cells hold great potential to destroy malignant cells. However, a peculiar ecosystem also nurses malignant clones; thus, the regulation and therapeutic activation of anti-angiogenesis with the aim of modulating the function of malignant vessels as immune gatekeepers in the cancer niche still represent evolving avenues in oncology. The functional characterization of molecular targets for pharmacological and immunological tumor therapy in the malignant advanced neoplasia pioneered the potential to elucidate the expression of immunosuppressive proteins by clonal cells. Thus, the activation of oncogenic signaling that can be interrupted by combinatorial approaches targeting the immune-patrolling cells and the vascular system at the same time. This chapter aims to review the regulation and therapeutic intervention for immunotherapy, starting from a robust pathobiological background. A combinatorial approach aims to unleash anti-tumor immunity while halting the cancer-associated angiogenesis. The need for an immunogram has also been uncovered to be the basis for next generation immunotherapy and immunodiagnostic.