Osteosarcoma (OSA) is the most common primary bone tumour of dogs and humans and is aggressively metastatic with a poor prognosis. Dogs serve as valuable comparative model for human OSA, aiding in evaluating novel therapeutic interventions due to similarities in clinical presentation, genetic complexity, and therapeutic management. Despite surgery and chemotherapy, many patients still develop pulmonary metastases, suggesting the presence of micro tumour cells, circulating in the blood which are not being eradicated by current treatment approaches. Being an immunogenic tumour, immunotherapy using autologous or heterologous vaccines targeting circulating tumour cells may inhibit the progression of malignant osteosarcoma, particularly pulmonary metastasis. Evidence suggest there is a link between acquired and innate immunity during progression of OSA. We review the rationale for targeting one or both immune system components, highlighting the complex crosstalk network among them in the biology of OSA. Further, we explore the use of dogs suffering from OSA in the clinical development of vaccine-based immunotherapies with potential translation into human medicine.