Therapeutic potential of oncolytic viruses in hematopoietic malignancies: from preclinical insights to clinical realities

While certain forms of lymphoma—such as classical Hodgkin lymphoma—are classified as curable, with over half of all patients achieving remission following first-line therapy, a significant proportion of patients still suffer from relapsed or refractory disease. Through autologous stem cell transplantation (ASCT) and chimeric antigen receptor (CAR) T-cell therapy can significantly improve survival rates, their widespread clinical utility is constrained by logistical bottlenecks, manufacturing complexities, and high financial burdens. Similarly, antibody-drug conjugates and bispecific antibodies have achieved striking success against hematologic malignancies, but their clinical adoption is often hindered by the requirement for continuous infusion. Consequently, systemically delivered oncolytic viruses engineered to express immunotherapeutic elements have emerged as highly innovative alternatives. This review provides a comprehensive overview of the current landscape and outlines the therapeutic potential of oncolytic virotherapy in the fight against hematopoietic malignancies. We cross-examined a robust dataset of over 100 preclinical investigations to critically assess the therapeutic efficacy and safety profiles of more than ten diverse oncolytic virus platforms developed for blood cancer treatment, alongside multiple early-phase clinical trials that are completed or currently underway. By synthesizing these preclinical and clinical data, we propose three critical development pathways—enhancing target specificity, arming viral vectors, and designing synergistic combination regimens—to accelerate the translation of clinically viable oncolytic viruses for hematologic oncology.