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

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 () and Jiankai Liang ()
Additional contact information
Zhen Fan: Sun Yat-sen University
Ying Liu: The Third Affiliated Hospital of Sun Yat-sen University
Xueying Lin: Sun Yat-sen University
Jifu Zhang: Sun Yat-sen University
Jiehong Chen: Sun Yat-sen University
Shiming Yi: Sun Yat-sen University
Cheng Hu: The Third Affiliated Hospital of Sun Yat-sen University
Xincheng Liu: Sun Yat-sen University
Cui Guo: Sun Yat-sen University
Cuiying Xu: Sun Yat-sen University
Xiaoyu Chen: Sun Yat-sen University
Xuyan Tian: Sun Yat-sen University
Xuanming Liang: Sun Yat-sen University
Yang Liu: Sun Yat-sen University
Linyi Hu: Sun Yat-sen University
Shanyu Huang: Sun Yat-sen University
Li Guo: Sun Yat-sen University
Wenbo Zhu: Sun Yat-sen University
Jun Hu: Sun Yat-sen University
Guangmei Yan: Sun Yat-sen University
Yuan Lin: Sun Yat-sen University
Jing Cai: Sun Yat-sen University
Jiankai Liang: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61439-0

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