Here, we show that cabozantinib can (a) modulate the phenotype of tumor cells, making them more susceptible to T cell-mediated lysis, (b) modify the composition of the peripheral and tumor microenvironment immune compartments, (c) alter immune cell function, and (d) induce sustained CD4+ and CD8+ T cell-dependent tumor regression when combined with a poxviral-based cancer vaccine. The gene discussed is CD8A; the disease is cancer.