Abstract
The success of cancer immunotherapies is predicated on the targeting of highly expressed neoepitopes, which preferentially favours malignancies with high mutational burden. Here we show that early responses by type-I interferons mediate the success of immune checkpoint inhibitors as well as epitope spreading in poorly immunogenic tumours and that these interferon responses can be enhanced via systemic administration of lipid particles loaded with RNA coding for tumour-unspecific antigens. In mice, the immune responses of tumours sensitive to checkpoint inhibitors were transferable to resistant tumours and resulted in heightened immunity with antigenic spreading that protected the animals from tumour rechallenge. Our findings show that the resistance of tumours to immunotherapy is dictated by the absence of a damage response, which can be restored by boosting early type-I interferon responses to enable epitope spreading and self-amplifying responses in treatment-refractory tumours.
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Data availability
The main data supporting the results in this study are available within the paper and its Supplementary Information and provided as supplementary source data. Raw data for sequencing results can be found at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE255666. Source data are provided with this paper.
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Acknowledgements
We thank G. Moore for assistance with veterinary animal experiments; D. Li and Biostatistics and Computational Biology Shared Resource for statistical support; L. Fagman and K. Young for help with large animals; and A. Dongtao Fu of the UF Molecular Pathology Core at the Department of Pathology, Immunology and Laboratory Medicine for assistance with genomics experiments. Cartoon images including those for mouse, canine, and schematics in figures were created with BioRender.com. This work was supported by federal awards W81XWH-17-1-0510, K08CA199224, R37CA251978, R01CA266857, R01FD007268 (FDA – OOPD, Office of Orphan Products Development), and P30CA247796; Florida Department of Health 20B11 (Bankhead Coley) and 20L07 (Live Like Bella) awards; and foundation grants from CureSearch (Catapult Award), Alex’s Lemonade Stand (R Accelerated Award), Rally Foundation, Hyundai Hope on Wheels (Hope Scholar Award), Stop Children’s Cancer and the Bonnie R. Freeman Professorship for Pediatric Oncology Research, Danny’s Dream, the Medulloblastoma Initiative (MBI) and Cure Group 4 Medulloblastoma Consortium, Ians Friends Foundation, and the National Pediatric Cancer Foundation.
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S.Q., B.W. and B.D.S. designed and performed the experiments, interpreted the data and co-wrote the paper. D.Z. conducted experimental studies and generated RNA vaccine reagents. J.M., F.W. and J.C.-R. conducted experiments. A.G. assisted with experiments and co-wrote the paper. A.D., C.Z., C.M., A.K., C.X., G.J., R.L., S.M., X.M., R.S.F.M., C.v.R., D.T.N., L.E., N.T., A.B., H.G., Y.C., E.O-R, C.R. and D.S. conducted/assisted with experiments. J.H. provided resources and oversight. S.C.-J. led canine studies. K.F. led H&E organ analyses. N.L.S., W.G.S., M.R., J.A.L. and C.T.F. provided critical resources and oversight. J.-H.L. oversaw statistical analyses. D.A.M. provided key resources and oversight. P.C. and H.R.M.-G. designed and performed experiments, interpreted data and co-wrote the paper. E.J.S. conceived and designed studies, performed experiments, provided resources and co-wrote the paper.
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D.A.M. and C.T.F. hold an ownership interest in iOncologi, Inc. W.G.S. holds interest in Aurita, Inc. E.J.S. is a paid consultant for Siren Biotechnology and serves on the external advisory board of Nature’s Toolbox with stock options. The paper discusses pending patent applications from S.Q., J.M., A.G., W.G.S., M.R., D.A.M., P.C., H.R.M.-G. and E.J.S, some of which are licensed to iOncologi, Inc. H.R.M.-G. and E.J.S. receive royalty payments from iOncologi, Inc.
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Qdaisat, S., Wummer, B., Stover, B.D. et al. Sensitization of tumours to immunotherapy by boosting early type-I interferon responses enables epitope spreading. Nat. Biomed. Eng 9, 1437–1452 (2025). https://doi.org/10.1038/s41551-025-01380-1
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DOI: https://doi.org/10.1038/s41551-025-01380-1
