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Background Within cancer immunotherapy, oncolytic viruses (OVs) are recognized as a promising and robust treatment approach. This study presents the potential of Infectious Bursal Disease Virus (IBDV), an avian-specific pathogen with no known human zoonosis, as a novel therapeutic agent.Methods We assessed IBDV’s efficacy against several cancer types, including glioblastoma (CT-2A, patient-derived glioblastoma stem cells), melanoma (B16-F10), colorectal carcinoma (CT-26), and B-cell lymphoma (A20). We have evaluated the infectivity, cytotoxicity, replication kinetics, and analyzed the expression of pro-inflammatory and anti-viral (IFN-I/IFN-III) cytokine responses in all tumoral models following viral infection, in comparison to those elicited by a very well-known OV, Newcastle disease virus (NDV). We further evaluated IBDV’s anti-tumor effects in preclinical glioblastoma, colon, melanoma, and B-cell lymphoma models using immunocompetent mice. Immunological responses to IBDV virotherapy were analyzed locally, in the tumor microenvironment (TME) and systemically (in tumor-draining and distal lymph nodes) via spectral flow cytometry.Results Results demonstrate that IBDV significantly exhibits oncolytic activity both in vitro and in vivo, effectively infecting, replicating in, and killing all cancer models, while inducing type-I/III IFN responses and enhancing pro-inflammatory (IL-1β and IL-6) responses. Notably, in melanoma (B16-F10) and glioblastoma (CT-2A) in vivo models, IBDV treatment delayed tumor growth and improved overall survival compared to PBS-treated mice, while complete tumor elimination was achieved in 30% of colorectal carcinoma (CT-26) and 60% B-cell lymphoma (A20) engrafted mice. In the A20 lymphoma model, a bilateral tumor setup was also used to assess abscopal effects. IBDV was injected in only one tumor, and delayed growth was observed in the contralateral, untreated tumor, indicating partial systemic immune activation. Overall, IBDV virotherapy elicited robust innate and adaptive immune responses within the TME, disrupting tumor immunotolerance. This was evidenced by the elevated ratios of M1/M2 and CD8+/Treg immune cell populations upon IBDV treatment compared to PBS-treated mice. In melanoma and colorectal carcinoma models, there was an upregulation of immunosuppressive markers on both CD4+ and CD8+ T cells in TME and tumor-draining lymph nodes.Conclusions These findings highlight IBDV’s potential as a robust OV and suggest combining IBDV treatment with therapies targeting co-inhibitory markers to enhance efficacy.