PDF(Pubmed)
Abstract：
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.
摘要：
对溶瘤病毒疗法的反应中异质性的存在对临床有效性构成了障碍，因为对这种治疗的抗性可以通过抑制病毒在肿瘤内的传播而发生，可能导致治疗失败。这里我们显示4-辛基衣康酸（4-OI），克雷布斯循环代谢产物衣康酸酯的化学衍生物，在包括人和鼠抗性癌细胞系在内的各种模型中增强VSVΔ51的溶瘤病毒疗法，三维（3D）患者来源的结肠肿瘤和器官型脑肿瘤切片。此外，4-OI与VSVA51组合改善抗性鼠结肠肿瘤模型中的治疗结果。机械上,我们发现4-OI通过修饰MAVS和IKKβ中的半胱氨酸残基而独立于NRF2/KEAP1轴抑制癌细胞的抗病毒免疫。我们提出，代谢物衍生药物与溶瘤病毒试剂的组合可以通过直接干扰I型IFN和NF-κB介导的抗病毒反应来大大提高抗癌治疗效果。
