Overcoming Barriers to Clinical Translation: MG1 Maraba Virus as an Emerging Platform for Oncolytic Immunotherapy

Oncolytic viruses (OVs) exploit key hallmarks of cancer to selectively replicate in malignant cells, leading to tumor cell lysis, modulation of the tumor microenvironment, and induction of antitumor immunity. These viral platforms have been engineered to enhance tumor specificity, intratumoral spread, and immunotherapeutic efficacy. Among them, rhabdoviruses, particularly vesiculoviruses, have emerged as promising candidates due to their rapid replication, high titers, and amenability to genetic manipulation. Maraba virus, a recently identified vesiculovirus, is a single-stranded negative-sense RNA virus with a favorable safety profile and minimal pre-existing immunity in humans. It demonstrates selective tumor tropism partly through low-density lipoprotein receptor (LDLR)-mediated entry and impaired antiviral responses in cancer cells. Genetic engineering of the wild-type Maraba virus led to the development of the MG1 strain, characterized by enhanced tumor selectivity, increased replication capacity, and potent cytolytic activity. Preclinical studies have demonstrated its efficacy as a monotherapy, a cancer vaccine vector expressing tumor-associated antigens, and in combination with chemotherapy and immune checkpoint inhibitors. MG1 also reshapes the tumor microenvironment, converting immunologically "cold" tumors into "hot" tumors, thereby enhancing immune-mediated tumor clearance. Compared to vesicular stomatitis virus, Maraba virus exhibits improved safety and reduced neurovirulence while maintaining strong oncolytic potential. This review aims to comprehensively summarize the biological characteristics of the MG1 Maraba virus, its genetic development, mechanisms of action, and current preclinical and clinical applications as a novel oncolytic immunotherapeutic agent.