Abstract: An engineered vaccinia virus, a pharmaceutical composition containing the same, and methods for use in treating a subject in need using the same are provided. The engineered vaccinia virus includes a mutated viral sequence and a heterologous sequence. The mutated viral sequence is used for selective replication in tumor cells and/or activation of immune cells. The heterologous sequence encodes an immune co-stimulatory pathway activating molecule, immunomodulator gene, a truncated viral envelope gene, and/or a tumor suppressor. The heterologous sequence is stably incorporated into the genome of the engineered vaccinia virus. The pharmaceutical composition includes an effective amount of the engineered vaccinia virus and a pharmaceutical acceptable vehicle. The methods for use in treating the subject in need include administering the engineered vaccinia virus to the subject.