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

• Published in: Nature communications Vol. 16; no. 1; pp. 6136 - 18
• Main Authors: Fan, Zhen, Liu, Ying, Lin, Xueying, Zhang, Jifu, Chen, Jiehong, Yi, Shiming, Hu, Cheng, Liu, Xincheng, Guo, Cui, Xu, Cuiying, Chen, Xiaoyu, Tian, Xuyan, Liang, Xuanming, Liu, Yang, Hu, Linyi, Huang, Shanyu, Guo, Li, Zhu, Wenbo, Hu, Jun, Yan, Guangmei, Lin, Yuan, Cai, Jing, Liang, Jiankai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.07.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/127/1213; 631/250/580/1884/2323; 631/326/596/2561; 631/67/1059/2325; 631/67/327; 96; 96/21; 96/31; 96/47; 96/63; 96/95; Animal models; Animals; Anticancer properties; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell activation; Cell differentiation; Cell Line, Tumor; Chemokines; Cytokines; Dendritic cells; Dendritic Cells - immunology; Disease Models, Animal; Effectiveness; FDA approval; Feedback loops; Female; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immunological memory; Immunology; Immunotherapy; Infections; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Interferon-gamma - metabolism; Interleukin 18; Interleukin 18 receptors; Interleukin-18 - genetics; Interleukin-18 - immunology; Interleukin-18 - metabolism; Intravenous administration; Ligands; Lymphocytes; Lymphocytes T; Malignancy; Melanoma; Metastases; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Neoplasms - immunology; Neoplasms - therapy; Oncolysis; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; PD-L1 protein; Positive feedback; Proteins; Receptors; Receptors, Interleukin-18 - genetics; Receptors, Interleukin-18 - metabolism; Science; Science (multidisciplinary); Solid tumors; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors; Viruses; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-61439-0

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 expressing a decoy-resistant IL-18 elicit anti-tumor immunity and long-term immunological memory against multiple refractory tumors in mice.