ArticleJournal for immunotherapy of cancer2025
Targeting TBK1 potentiates oncolytic virotherapy via amplifying ICAM1-mediated NK cell immunity in chemo-resistant colorectal cancer.
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.Translational oncology · 2026Review
- Engineered oncolytic virus armed with anti-PCSK9 scFv boosts long-term CD8Cell reports. Medicine · 2026Article
- Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review).International journal of oncology · 2026Review
- Review
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Authors and funding
14 authors.
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Abstract
backgroundTumor 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.
methodsWe 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.
resultsWe 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, which mediated the activation of the type I interferon pathway and impaired viral replication. TBK1 inhibition enhanced intratumor viral replication and direct oncolysis effect in vitro and augmented the antitumor immunity elicited by OVs in vivo. Immune cell profiles presented that OV/TBK1i combination reshaped the tumor microenvironment and especially activated the NK cell response. Immune cell depletion studies demonstrated that NK cells were required for the synergistic therapeutic activity of the OV/TBK1i combination. Mechanistically, TBK1 inhibition synergized with VSVΔ51 to increase ICAM1 expression in a RIPK1-dependent manner, promoting NK cell-mediated tumor killing.
conclusionThis study presents a promising approach for treating chemo-resistant CRC by combining OVs and TBK1i.
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