Suppression of multiple mouse models of refractory malignancies by reprogramming IL-18 ligand-receptor interaction

作者：Zhen Fan, Ying Liu, Xueying Lin, Jifu Zhang, Jiehong Chen, Shiming Yi, Cheng Hu, Xincheng Liu, Cui Guo, Cuiying Xu, Xiaoyu Chen, Xuyan Tian, Xuanming Liang, Yang Liu, Linyi Hu, Shanyu Huang, Li Guo, Wenbo Zhu, Jun Hu, Guangmei Yan, Yuan Lin, Jing Cai, Jiankai Liang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61439-0 · 被引用次数：5 · 研究领域：Virus-based gene therapy research、CAR-T cell therapy research、Immunotherapy and Immune Responses

Achieving a cure is an urgent need for patients with advanced solid tumors. Here, we discover that oncolytic virus (OV) infection enhances IL-18 receptor expression but fails to increase IL-18 ligand expression. Therefore, we engineer armed oncolytic alphavirus M1 expressing wild-type IL-18 (wtIL-18) or a mutant variant (mutIL-18) that evades IL-18 binding protein (IL-18BP) while maintaining IL-18 receptor (IL-18R) binding. Intravenous administration of M1-mutIL-18 suppresses the growth of multiple advanced solid tumors in C57BL/6 and BALB/c mouse models and promotes long-term systemic immune memory. Mechanistically, armed M1-mutIL-18 enhances directed clonal expansion and differentiation of CD8+ T cells and sustains IFN-γ production. Thus, armed M1-mutIL-18 promotes dendritic cell (DC) activation, priming and activation of CD8+ T cells in lymphatic organs, and infiltration of IL-18R+ CD8+ T cells in the tumor microenvironment, establishing a positive feedback loop. We further show that a PD-L1 inhibitor enhances the anti-tumor efficacy of mutIL-18 OVs. These results highlight the importance of the IL-18 pathway in oncolytic virus therapy and implicate reprogramming ligand-receptor interaction as an effective strategy for immunotherapy. Immunotherapy holds great potential, although strategies for durable responses against solid tumors are still needed. Here, the authors combine oncolytic virus (OV) engineering and reprogramming of the IL-18 pathway, showing that armed OVs exp...