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.

溶瘤病毒疗法反应中存在的异质性对临床有效性构成了障碍，因为通过抑制肿瘤内的病毒传播可能会出现对该治疗的耐药性，从而可能导致治疗失败。在这里，我们展示了衣康酸 4-辛酯 (4-OI) 是克雷布斯循环衍生代谢物衣康酸的化学衍生物，可在各种模型中增强 VSVΔ51 的溶瘤病毒治疗，包括人类和小鼠耐药癌细胞系、三维 (3D) 患者-衍生的结肠肿瘤样细胞和器官型脑肿瘤切片。此外，4-OI 与 VSVΔ51 组合可改善耐药小鼠结肠肿瘤模型的治疗效果。从机制上讲，我们发现 4-OI 通过独立于 NRF2/KEAP1 轴修饰 MAVS 和 IKKβ 中的半胱氨酸残基来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极大地改善抗癌治疗结果。