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Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways.

Naziia KurmashevaAida SaidBoaz WongPriscilla KindermanXiaoying HanAnna H F RahimicAlena KressMadalina E Carter-TimofteEmilia HolmDemi van der HorstChristoph F KollmannZhenlong LiuChen WangHuy-Dung HoangElina KovalenkoMaria ChrysopoulouKrishna Sundar TwayanaRasmus N OttosenEsben B SvenningsenFabio BegniniAnders E KiibFlorian E H KrommHauke Johannes WeissDaniele Di CarloMichela MuscoliniMaureen HigginsMirte van der HeijdenAngelina BardoulTong TongAttila OzsvarWen-Hsien HouVivien R SchackChristian Kanstrup HolmYunan ZhengMelanie RuzekJoanna M KaluckaLaureano de la VegaWalid A M ElgaherAnders Rosendal KorshoejRongtuan LinJohn HiscottThomas B PoulsenLuke Anthony John O'NeillDominic Guy RoyMarkus M RinschenNadine van MontfoortJean-Simon DialloHenner F FarinTommy AlainDavid Olagnier
Published in: Nature communications (2024)
The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.
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