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Checkpoint inhibitors have revolutionized cancer treatment, but a significant proportion of patients do not respond to these therapies, underscoring the need for alternative strategies. Although gene therapy has made substantial strides, its application in solid tumors remains underexplored, with limited treatments approved. Here, we further investigated a gene therapy approach with non-replicating adenoviral vectors encoding the alternate reading frame (ARF) and interferon beta (IFNb) and tested it in a clinically relevant setting. We previously showed that this combined gene therapy induces immunogenic cell death in melanoma models, and now, we utilize patient-derived organotypic tumor spheroids (PDOTS), a model that closely recapitulates the immune environment of tumors, to test its effects using patient tumors. Our results demonstrate, for the first time, the effectiveness of using PDOTS to evaluate viral-vector-based gene therapies. While the addition of anti-PD-1 did not enhance therapeutic outcomes, the gene therapy alone suppressed tumor growth and triggered antitumor immune responses across different cancer models, notably those with low immunogenicity and specific genome profiles. These findings suggest that this gene therapy could serve as a valuable alternative for patients not responsive to checkpoint inhibitors and who have solid tumors with limited treatment and impaired p53-ARF-MDM2 pathways, such as liposarcomas.