Targeting TBK1 potentiates oncolytic virotherapy via amplifying ICAM1-mediated NK cell immunity in chemo-resistant colorectal cancer

作者：Xin Guo, Huolun Feng, Zhihui Xi, Ji Zhou, Zuda Huang, Jieqing Guo, Jiabin Zheng, Zejian Lyu, Yongfeng Liu, Jianlong Zhou, Yucheng Zhang, Yuhan Zhang, Yong Li, Fan Xing · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-011455 · 被引用次数：6 · 研究领域：Virus-based gene therapy research、interferon and immune responses、Immune Cell Function and Interaction

BACKGROUND: Tumor resistance is the primary reason for treatment failure in patients with cancer, while oncolytic viruses (OVs), as a novel therapy, have been rapidly advancing through clinical evaluation and are typically assessed in recurrent tumors that are refractory to standard chemotherapy. However, whether the adaptive process that fosters chemotherapy resistance influences the efficacy of OV therapy is unknown. METHODS: We analyzed chemo-resistant colorectal cancer (CRC) using in vitro, in vivo, and patient-derived organoid models to assess sensitivity to OVs. Through RNA sequencing analysis and immunohistochemistry were performed in clinical samples that indicated TANK-binding kinase 1 (TBK1) expression. Using single-cell RNA sequencing, flow cytometry, and in vivo neutralization assays to demonstrate that the combination of TBK1 inhibitor (TBK1i) and OVs reprograms the tumor immune microenvironment, particularly by activating natural killer (NK) cells. Through RNA sequencing analysis, we identified intercellular cell adhesion molecule-1 (ICAM-1) as a potential target responsible for NK cell activation. Subsequently, we designed and conducted rescue experiments, both in vitro and in vivo, to validate the influence of ICAM-1 on NK cell activity. RESULTS: We demonstrated that chemo-resistant CRC showed decreased sensitivity to the OV in vitro, in vivo, and patient-derived organoids. Further investigation revealed aberrant activation of TBK1 in chemo-resistant CRC, whic...