Targeting KIF18A triggers antitumor immunity and enhances efficiency of PD-1 blockade in colorectal cancer with chromosomal instability phenotype
Abstract Colorectal cancer with chromosomal instability (CIN+) phenotype is immunosuppressive and refractory to immune checkpoint blockade (ICB) therapy. Recently, KIF18A is found to be a mitotic vulnerability in chromosomally unstable cancers, but whether targeting KIF18A affects antitumor immunity...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02437-5 |
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| _version_ | 1849733397034827776 |
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| author | Gang Liu Yan Zhang Zhen Cao Zhanwei Zhao |
| author_facet | Gang Liu Yan Zhang Zhen Cao Zhanwei Zhao |
| author_sort | Gang Liu |
| collection | DOAJ |
| description | Abstract Colorectal cancer with chromosomal instability (CIN+) phenotype is immunosuppressive and refractory to immune checkpoint blockade (ICB) therapy. Recently, KIF18A is found to be a mitotic vulnerability in chromosomally unstable cancers, but whether targeting KIF18A affects antitumor immunity in CIN+ colorectal cancer is unknown. In our study, western blot, cell viability assay, transwell migration and invasion assays, flow cytometry, animal model, immunohistochemistry (IHC) staining, reverse transcription–quantitative PCR (RT-qPCR) and ELISA assay were conducted to evaluate the potential function of KIF18A in CIN+ colorectal cancer. We found that KIF18A inhibition by short hairpin RNAs (ShRNAs) or small inhibitor AM-1882 suppressed proliferation, migration, invasion and tumor growth and metastasis of CIN+ colorectal cancer cells in vitro and in vivo. Moreover, targeting KIF18A disrupted cell-cycle progression and induced G2/M arrest in CIN+ colorectal cancer cells. In addition, KIF18A inhibition promoted immune infiltration and activation in CIN+ colorectal tumors. KIF18A inhibition suppressed proliferation of Tregs and increased infiltration and activation of cytotoxic CD8+ T cells in CIN+ colorectal tumors. Mechanically, KIF18A inhibition stimulated type I IFN signaling and cGAS-STING activation in CIN+ colorectal tumors. Finally, targeting KIF18A enhanced PD-1 blockade efficiency in CIN+ colorectal tumors through T cells. Our data elucidated a novel role of KIF18A in antitumor immunity of CIN+ colorectal cancer. |
| format | Article |
| id | doaj-art-efe00b9bd7784837acdfd16ca5e8a7df |
| institution | DOAJ |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-efe00b9bd7784837acdfd16ca5e8a7df2025-08-20T03:08:02ZengNature Publishing GroupCell Death Discovery2058-77162025-04-0111111110.1038/s41420-025-02437-5Targeting KIF18A triggers antitumor immunity and enhances efficiency of PD-1 blockade in colorectal cancer with chromosomal instability phenotypeGang Liu0Yan Zhang1Zhen Cao2Zhanwei Zhao3Senior Department of General Surgery, Chinese PLA General HospitalSenior Department of General Surgery, Chinese PLA General HospitalSenior Department of General Surgery, Chinese PLA General HospitalSenior Department of General Surgery, Chinese PLA General HospitalAbstract Colorectal cancer with chromosomal instability (CIN+) phenotype is immunosuppressive and refractory to immune checkpoint blockade (ICB) therapy. Recently, KIF18A is found to be a mitotic vulnerability in chromosomally unstable cancers, but whether targeting KIF18A affects antitumor immunity in CIN+ colorectal cancer is unknown. In our study, western blot, cell viability assay, transwell migration and invasion assays, flow cytometry, animal model, immunohistochemistry (IHC) staining, reverse transcription–quantitative PCR (RT-qPCR) and ELISA assay were conducted to evaluate the potential function of KIF18A in CIN+ colorectal cancer. We found that KIF18A inhibition by short hairpin RNAs (ShRNAs) or small inhibitor AM-1882 suppressed proliferation, migration, invasion and tumor growth and metastasis of CIN+ colorectal cancer cells in vitro and in vivo. Moreover, targeting KIF18A disrupted cell-cycle progression and induced G2/M arrest in CIN+ colorectal cancer cells. In addition, KIF18A inhibition promoted immune infiltration and activation in CIN+ colorectal tumors. KIF18A inhibition suppressed proliferation of Tregs and increased infiltration and activation of cytotoxic CD8+ T cells in CIN+ colorectal tumors. Mechanically, KIF18A inhibition stimulated type I IFN signaling and cGAS-STING activation in CIN+ colorectal tumors. Finally, targeting KIF18A enhanced PD-1 blockade efficiency in CIN+ colorectal tumors through T cells. Our data elucidated a novel role of KIF18A in antitumor immunity of CIN+ colorectal cancer.https://doi.org/10.1038/s41420-025-02437-5 |
| spellingShingle | Gang Liu Yan Zhang Zhen Cao Zhanwei Zhao Targeting KIF18A triggers antitumor immunity and enhances efficiency of PD-1 blockade in colorectal cancer with chromosomal instability phenotype Cell Death Discovery |
| title | Targeting KIF18A triggers antitumor immunity and enhances efficiency of PD-1 blockade in colorectal cancer with chromosomal instability phenotype |
| title_full | Targeting KIF18A triggers antitumor immunity and enhances efficiency of PD-1 blockade in colorectal cancer with chromosomal instability phenotype |
| title_fullStr | Targeting KIF18A triggers antitumor immunity and enhances efficiency of PD-1 blockade in colorectal cancer with chromosomal instability phenotype |
| title_full_unstemmed | Targeting KIF18A triggers antitumor immunity and enhances efficiency of PD-1 blockade in colorectal cancer with chromosomal instability phenotype |
| title_short | Targeting KIF18A triggers antitumor immunity and enhances efficiency of PD-1 blockade in colorectal cancer with chromosomal instability phenotype |
| title_sort | targeting kif18a triggers antitumor immunity and enhances efficiency of pd 1 blockade in colorectal cancer with chromosomal instability phenotype |
| url | https://doi.org/10.1038/s41420-025-02437-5 |
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