Cancer immunotherapy has transformed modern oncology, yet durable responses remain limited for many patients due to immune exclusion, adaptive resistance, and tumor heterogeneity. Oncolytic viruses (OVs) have emerged as a novel class of immunotherapeutics that unify direct tumor cytolysis with stimulation of antitumor immunity. By inducing immunogenic cell death (ICD) and releasing tumor-associated antigens (TAAs), OVs remodel the tumor microenvironment (TME) into an inflamed and immune-permissive niche capable of enabling systemic immune activation. Rapid advances in viral engineering have strengthened the translational potential of OVs through tumor-selective gene deletions, tumor-specific promoters, microRNA-based detargeting, and receptor-retargeting strategies that collectively enhance safety, specificity, and intratumoral propagation. Next-generation OVs are increasingly “armed” with immunostimulatory payloads—including cytokines, chemokines, checkpoint inhibitors, bispecific T-cell engagers, and suicide gene systems—allowing localized immune modulation with reduced systemic toxicity. These innovations have propelled significant clinical progress, exemplified by the approvals of talimogene laherparepvec (T-VEC), G47Δ, and H101, and have driven a surge of combination trials integrating OVs with immune checkpoint blockade, adoptive cell therapies, radiotherapy, and targeted therapies to overcome multilayered tumor immune resistance. Despite this momentum, clinical implementation remains challenged by antiviral immunity, heterogeneous viral distribution, stromal barriers, and dynamic interferon (IFN) signaling in the TME. Emerging delivery approaches, including carrier cell systems, nanotechnology-enabled viral shielding, and synthetic virology platforms, offer promising solutions to these limitations. Oncolytic virotherapy is rapidly evolving into a multifunctional immunotherapeutic platform capable of reshaping antitumor responses at both local and systemic levels. By integrating advanced viral engineering with rational combination strategies and innovative delivery technologies, OVs hold substantial potential to overcome current barriers in cancer immunotherapy and advance precision oncology. Continued translational research will be essential to fully harness their therapeutic impact and broaden their clinical applicability.
Fayyad‐Kazan et al. (Tue,) studied this question.