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  • Systematic review of the use of Newcastle virus in cancer immunotherapy: molecular mechanisms and clinical perspectives

  • Khorshid Rabiei Samani ,1,*
    1. Faculty of Veterinary Medicine, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran


  • Introduction: Cancer is one of the major public health challenges, and immunotherapy, despite significant advances, faces limitations such as drug resistance and immunosuppressive tumor microenvironment. Newcastle disease virus (NDV) is an avian paramyxoviridae virus that selectively infects and kills tumor cells. The unique feature of NDV is the lack of pre-existing immunity in humans, which allows for repeated administration. Among the multitude of oncolytic agents, NDV occupies a special place. This virus, which mainly infects poultry, has two distinctive features; first, a significant lack of pathogenicity in healthy humans due to cellular differentiation and a strong interferon response in normal cells, and second, a strong selective toxicity for malignant cells. The mechanism of this selectivity is mainly due to the disruption of type I interferon signaling pathways and the overexpression of sialic acid receptors on the surface of tumors. Unlike human viruses, which have neutralizing antibodies in the majority of the population, the human population is largely seropositive to NDV, which allows repeated systemic administration without loss of response. These features make NDV an ideal candidate for immunotherapy, especially in solid tumors that are resistant to conventional treatments. The aim of this systematic review is to investigate the mechanisms of NDV-based immunotherapy and its clinical applications in cancer treatment.
  • Methods: A systematic search was conducted in PubMed, Scopus, and Google Scholard with the keywords "Newcastle disease virus", "oncolytic virus", "immunotherapy", "tumor microenvironment", and "clinical trial" between 2000 and 2025. Original research articles, systematic reviews, and phase I/II clinical trials evaluating NDV in cancer treatment were included in the study. A total of 47 articles met the inclusion criteria.
  • Results: A total of 19 studies were analyzed. NDV selectively infects cancer cells by binding to sialic acid receptors overexpressed on tumor cells. Disruption of the type I interferon signaling pathway in tumor cells provides the basis for specific virus replication. Studies have shown that NDV induces apoptosis via intrinsic (mitochondrial) and extrinsic (death receptor) pathways, as well as autophagy and necroptosis. NDV converts the tumor microenvironment from a “cold” (immunosuppressive) to a “hot” (inflammatory) state by activating dendritic cells and macrophages. The virus is able to activate NK cells, and a recent study showed that NDV facilitates the induction of pantoptosis (a type of inflammatory cell death) in colorectal cancer cells dependent on gasdermin B by increasing the expression of granzyme A in NK cells. NDV induces immunogenic cell death, stimulates the release of tumor antigens and DAMPs, and activates the response of cytotoxic T lymphocytes. Genetic engineering strategies using the reverse genetics system have enabled the design of recombinant viruses (rNDV) that express immune-stimulating genes such as GM-CSF, interleukins (IL-2, IL-7, IL-12, IL-15), and TRAIL.
  • Conclusion: Overall, the evidence gathered in this systematic review suggests that Newcastle virus is more than a simple cytolytic agent, but a potent modulator of innate and adaptive immunity. Its ability to simultaneously induce apoptosis, autophagy, and pantoptosis (via activation of gasdermin B) while releasing damage-associated molecular patterns (DAMPs) provides a platform for the development of long-lasting antitumor immunity. Recent advances in the engineering of recombinant NDV (rNDV) expressing immune-stimulating genes such as GM-CSF and interleukins, together with promising results from phase I/II trials in combination with checkpoint inhibitors, have opened up new horizons in the treatment of resistant tumors. However, challenges remain, such as dose optimization, reduction of low-grade side effects, and selection of biomarkers predictive of response to therapy. The future of NDV-based immunotherapy appears to lie in combination and personalized approaches, particularly for tumors with high mutational burden and cold immune microenvironments.
  • Keywords: Newcastle virus, cancer immunotherapy, oncolytic virus, tumor microenvironment

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