Reza Ghavimi, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
Leila Rahimian, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
Mohsen Mohammadi, Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Ojasvi Dutta, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
Harikrishnan Mohan, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
Vladimir Chouljenko, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
Tolulope O. Omolekan, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA
Jean Christopher Chamcheu, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; Department of Biological Sciences and Chemistry, College of Sciences and Engineering, Southern University and A&M College, Baton Rouge, LA 70813, USA; Department of Biological Sciences and Chemistry, College of Sciences and Engineering, Southern University and A&M College, Baton Rouge, Louisiana, USAFollow
Konstantin G. Kousoulas, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA; Division of Biotechnology and Molecular Medicine, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA

Document Type

Article

Publication Title

Viral Warriors: Unlocking The Immune System’s Potential With Oncolytic Viruses In Cancer Immunotherapy

Abstract

Oncolytic viruses (OVs) represent an exciting avenue in tumor immunotherapy, harnessing the power of viruses to overcome resistance and enhance immune responses. OVs achieve this by selectively targeting and destroying tumor cells. This cell lysis releases tumor-specific antigens (TAAs), effectively creating an in situ vaccine that educates the immune system. Moreover, OVs directly trigger both innate and adaptive immunity and can be genetically engineered to secrete immune-boosting factors. Early studies have shown promising synergistic antitumor effects when OVs are combined with other cancer therapies or immunotherapies. A key advantage of OVs is their capacity to reprogram the tumor microenvironment (TME), transforming immunologically inert “cold” tumors into actively inflamed “hot” tumors. This environmental shift is crucial for successful immunotherapy, as it allows for increased infiltration of immune cells, particularly cytotoxic T lymphocytes (CTLs), into the tumor. This comprehensive review covers the history, mechanisms, and potential combinatorial strategies involving OVs. It also addresses the challenges faced in their development and highlights current clinical trials exploring their role as potent immunotherapeutic agents.

First Page

Cancer remains a significant and challenging global health problem.1 Between 2022 and 2023, nearly 20 million new cancer cases were diagnosed worldwide, and approximately 9.7 million people died of the disease. The economic burden of cancer, including direct medical costs and indirect losses from reduced productivity, amounts to hundreds of billions of dollars annually.2 Projections suggest that the global cancer incidence will rise to 35 million new cases per year by 2050, driven largely by population growth and aging. These trends underscore the urgent need for enhanced cancer prevention, early detection, and equitable access to treatment across all regions.3 While conventional treatments like radiation, chemotherapy, and surgery have advanced, there is still a need for new, highly effective therapies. Recent decades have seen the rise of cancer immunotherapy, which aims to harness the body’s immune system to fight cancer. Oncolytic virotherapy, using oncolytic viruses (OVs), is an exciting frontier within this field.4,5,6 OVs are DNA- or RNA-based viruses engineered to selectively replicate within and lyse tumor cells while sparing healthy cells. This tumor-specific tropism offers a significant advantage over conventional cancer therapies by minimizing systemic toxicity. Although certain viruses like reovirus or parvovirus exhibit a degree of intrinsic oncotropism, many commonly used OVs lack inherent tumor selectivity, contributing to off-target toxicity and limiting clinical efficacy. Advanced genetic engineering strategies have been developed to overcome these limitations to enhance tumor specificity. These include the transcriptional regulation of immune evasion and replication genes via tumor-specific promoters, modification of viral envelope or entry-related proteins, and the incorporation of microRNA target sequences to restrict viral replication to malignant cells.7,8 Additionally, pharmacological approaches employing small molecules are being explored to enhance oncotropism. These agents function by suppressing antiviral defenses, upregulating viral receptors, or sensitizing tumor cells to viral replication, thereby augmenting therapeutic precision and efficacy.9 Many OVs are under active investigation for cancer therapy, including adenoviruses, herpes simplex viruses (HSVs), and measles viruses, among others. These viral agents are being explored for their capacity to selectively replicate within malignant cells and elicit antitumor immune responses, offering a promising avenue for novel therapeutic interventions10,11

Last Page

Concluding remarks and future perspectives A fundamental challenge in cancer treatment is the ability of cancer cells to evade the immune system through complex mechanisms, including the secretion of immunosuppressive factors, reduced presentation of tumor antigens, and the creation of an immunosuppressive tumor microenvironment (TME). Tumors can be broadly classified as immunologically “hot,” characterized by significant immune cell infiltration, or “cold,” with limited immune presence. Hot tumors are generally more responsive to immunotherapies. A key therapeutic goal is therefore to convert these cold tumors into inflamed hot ones to enhance antitumor immunity. OVs are emerging as a potent novel form of cancer immunotherapy capable of directly addressing this goal. By selectively infecting and lysing tumor cells in an immunogenic manner, OVs not only destroy cancer cells but also function as an in situ vaccine, releasing tumor-specific antigens and danger signals that activate both innate and adaptive immune responses. In recent decades, substantial advances have been achieved in the genetic engineering of OVs to enhance their potency, tumor selectivity, and safety, and improve delivery and production methods. This progress has positioned OVs as promising agents, demonstrating efficacy in both preclinical studies and clinical trials, either as monotherapies or in combination strategies. Despite these advancements, the widespread clinical adoption of OVs faces several specific challenges. These include achieving sufficient penetration and uniform spread of OVs throughout the heterogeneous TME, overcoming intrinsic or acquired resistance mechanisms in tumor cells, managing the variability in patient immune responses, and addressing the often-limited efficacy of OV monotherapy compared with combinations. Furthermore, systemic delivery of OVs is hindered by rapid clearance by the host immune system, including neutralization by preexisting or treatment-induced antibodies. While direct intratumoral injection bypasses some systemic challenges, it is not applicable to all tumor types or metastatic disease. To address these hurdles and amplify therapeutic effects, strategic combinations of OVs with other cancer treatments are essential. Genetic engineering enables OVs to function as versatile “Trojan horses,” delivering therapeutic transgenes directly to the tumor site. • Combination with conventional therapies: Combining OVs with chemotherapy or radiotherapy can yield synergistic effects. Chemotherapy can potentially reduce systemic immune clearance of OVs while increasing tumor cell susceptibility, and radiotherapy can enhance viral replication and spread within the tumor, leading to improved tumor control and survival. • Combination with targeted therapies: Integrating OVs with targeted agents can disrupt specific pro-survival pathways in cancer cells and potentially modulate the TME or immune responses to favor viral infection and activity. • Combination with immunotherapies: The synergism between OVs and other immunotherapies, such as ICIs, adoptive T cell therapies (like CAR-T cells), or bispecific T cell engagers (BiTEs), is particularly compelling. OVs can enhance the inflammatory state of the TME, increase antigen presentation, and recruit effector cells, thereby priming tumors for more effective attack by these targeted immunotherapies. These combinatorial strategies facilitate a more comprehensive and potentially personalized approach to cancer treatment. Ongoing preclinical and clinical trials are actively exploring these combinations, aiming to demonstrate enhanced response rates and broader applicability compared with single-agent therapies. The future of oncolytic virotherapy is exceptionally bright, holding the potential to become a cornerstone of cancer care. Its unique mechanism of action, combining direct tumor lysis with potent immune stimulation, offers a powerful means to overcome tumor resistance and modulate the immunosuppressive TME. Future research will focus on developing even more sophisticated armed OVs, optimizing delivery methods (especially systemic), identifying biomarkers predictive of response to guide personalized combination treatments, and further unraveling the intricate interactions within the tumor-virus-immune system axis. Continued investment and collaboration across research, clinical, and industry sectors are crucial to translating the immense promise of oncolytic virotherapy into improved outcomes for a wider range of cancer patients.

DOI

https://doi.org/10.1016/j.omton.2025.201100.

Publication Date

12-18-2025

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