Oncolytic virotherapy (OVT) is a promising cancer treatment that uses genetically engineered viruses to replicate within cancer cells and trigger an anti-tumor immune response. Vaccinia virus (VACV) has emerged as a potential candidate due to its ability to infect a wide range of cancer cells. This review discusses the mechanisms, benefits, and clinical trials of oncolytic VACVs, exploring the safety and efficacy of different viral backbones, their effects on the tumor microenvironment, and potential combinations with immunotherapy or traditional therapies. The review also addresses the prospects and challenges in the field of oncolytic VACVs, aiming to promote further research and application in cancer therapy. Key points include the selective self-replication and oncolysis of VACV in tumor cells, disruption of tumor vasculature, and activation of anti-tumor immune responses. The review highlights the construction of oncolytic VACV backbones through genome editing and the development of combination therapies, such as combining oncolytic VACVs with immunostimulatory genes, chimeric antigen receptor (CAR) T-cell therapy, and immune checkpoint blockade (ICB) therapy. Additionally, it discusses the potential of oncolytic VACVs in combination with radiotherapy, chemotherapy, and molecular targeted therapy. The clinical trials and delivery routes of oncolytic VACVs are also reviewed, emphasizing the need for repeated intravenous administration and the development of methods to enhance systemic delivery. The review concludes by addressing the challenges and future prospects of oncolytic VACVs in cancer therapy.Oncolytic virotherapy (OVT) is a promising cancer treatment that uses genetically engineered viruses to replicate within cancer cells and trigger an anti-tumor immune response. Vaccinia virus (VACV) has emerged as a potential candidate due to its ability to infect a wide range of cancer cells. This review discusses the mechanisms, benefits, and clinical trials of oncolytic VACVs, exploring the safety and efficacy of different viral backbones, their effects on the tumor microenvironment, and potential combinations with immunotherapy or traditional therapies. The review also addresses the prospects and challenges in the field of oncolytic VACVs, aiming to promote further research and application in cancer therapy. Key points include the selective self-replication and oncolysis of VACV in tumor cells, disruption of tumor vasculature, and activation of anti-tumor immune responses. The review highlights the construction of oncolytic VACV backbones through genome editing and the development of combination therapies, such as combining oncolytic VACVs with immunostimulatory genes, chimeric antigen receptor (CAR) T-cell therapy, and immune checkpoint blockade (ICB) therapy. Additionally, it discusses the potential of oncolytic VACVs in combination with radiotherapy, chemotherapy, and molecular targeted therapy. The clinical trials and delivery routes of oncolytic VACVs are also reviewed, emphasizing the need for repeated intravenous administration and the development of methods to enhance systemic delivery. The review concludes by addressing the challenges and future prospects of oncolytic VACVs in cancer therapy.