Inhibiting UPF1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense-mediated mRNA decay
Summary: Nonsense-mediated mRNA decay (NMD) is a conserved RNA surveillance mechanism. Inhibition of NMD leads to increased expression of tumor neoantigens encoded by genes with premature termination codons (PTCs), thereby enhancing tumor immunogenicity. In this study, we find that protein levels of...
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| Language: | English |
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Elsevier
2025-07-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725006904 |
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| author | Shengyu Zhu Yucong Bai Dongjing Zhang Changsheng Huang Xu Qian Pengcheng Li Tianci Xie Qi Wu Anyi Liu Tong Zhu Wangshuo Yang Xiaowei She Mao Li Zejun Rao Siqi Chen Lang Liu Chengxin Yu Xiang Liu Guihua Wang Guangyong Zhang Junbo Hu |
| author_facet | Shengyu Zhu Yucong Bai Dongjing Zhang Changsheng Huang Xu Qian Pengcheng Li Tianci Xie Qi Wu Anyi Liu Tong Zhu Wangshuo Yang Xiaowei She Mao Li Zejun Rao Siqi Chen Lang Liu Chengxin Yu Xiang Liu Guihua Wang Guangyong Zhang Junbo Hu |
| author_sort | Shengyu Zhu |
| collection | DOAJ |
| description | Summary: Nonsense-mediated mRNA decay (NMD) is a conserved RNA surveillance mechanism. Inhibition of NMD leads to increased expression of tumor neoantigens encoded by genes with premature termination codons (PTCs), thereby enhancing tumor immunogenicity. In this study, we find that protein levels of up-frameshift protein 1 (UPF1), a key factor in the NMD pathway, show significant differences in clinical tumor samples of microsatellite-stable (MSS) and microsatellite-unstable (MSI) colorectal cancer (CRC). UPF1 protein levels negatively regulate tumor immunogenicity and sensitivity to anti-PD-1 therapy in MSS and MSI CRC mouse models. Mechanistically, asymmetric di-methylation of UPF1 R433 by protein arginine methyltransferase 4 inhibits the autophagic degradation of UPF1, and inhibiting UPF1 R433 methylation can weaken NMD, thus increasing the immunogenicity and anti-PD-1 sensitivity of CRC, regardless of MSS or MSI status. Our study highlights the potential of combination strategies in CRC immunotherapy, promising to expand the beneficiaries of immunotherapy and provide insights for new therapeutic targets. |
| format | Article |
| id | doaj-art-9c12b097108e427f8975dffa37b63f5f |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-9c12b097108e427f8975dffa37b63f5f2025-08-20T03:24:44ZengElsevierCell Reports2211-12472025-07-0144711591910.1016/j.celrep.2025.115919Inhibiting UPF1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense-mediated mRNA decayShengyu Zhu0Yucong Bai1Dongjing Zhang2Changsheng Huang3Xu Qian4Pengcheng Li5Tianci Xie6Qi Wu7Anyi Liu8Tong Zhu9Wangshuo Yang10Xiaowei She11Mao Li12Zejun Rao13Siqi Chen14Lang Liu15Chengxin Yu16Xiang Liu17Guihua Wang18Guangyong Zhang19Junbo Hu20GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaDepartment of General Surgery, First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, ChinaGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China; Corresponding authorDepartment of General Surgery, First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China; Corresponding authorGI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China; Corresponding authorSummary: Nonsense-mediated mRNA decay (NMD) is a conserved RNA surveillance mechanism. Inhibition of NMD leads to increased expression of tumor neoantigens encoded by genes with premature termination codons (PTCs), thereby enhancing tumor immunogenicity. In this study, we find that protein levels of up-frameshift protein 1 (UPF1), a key factor in the NMD pathway, show significant differences in clinical tumor samples of microsatellite-stable (MSS) and microsatellite-unstable (MSI) colorectal cancer (CRC). UPF1 protein levels negatively regulate tumor immunogenicity and sensitivity to anti-PD-1 therapy in MSS and MSI CRC mouse models. Mechanistically, asymmetric di-methylation of UPF1 R433 by protein arginine methyltransferase 4 inhibits the autophagic degradation of UPF1, and inhibiting UPF1 R433 methylation can weaken NMD, thus increasing the immunogenicity and anti-PD-1 sensitivity of CRC, regardless of MSS or MSI status. Our study highlights the potential of combination strategies in CRC immunotherapy, promising to expand the beneficiaries of immunotherapy and provide insights for new therapeutic targets.http://www.sciencedirect.com/science/article/pii/S2211124725006904CP: CancerCP: Immunology |
| spellingShingle | Shengyu Zhu Yucong Bai Dongjing Zhang Changsheng Huang Xu Qian Pengcheng Li Tianci Xie Qi Wu Anyi Liu Tong Zhu Wangshuo Yang Xiaowei She Mao Li Zejun Rao Siqi Chen Lang Liu Chengxin Yu Xiang Liu Guihua Wang Guangyong Zhang Junbo Hu Inhibiting UPF1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense-mediated mRNA decay Cell Reports CP: Cancer CP: Immunology |
| title | Inhibiting UPF1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense-mediated mRNA decay |
| title_full | Inhibiting UPF1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense-mediated mRNA decay |
| title_fullStr | Inhibiting UPF1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense-mediated mRNA decay |
| title_full_unstemmed | Inhibiting UPF1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense-mediated mRNA decay |
| title_short | Inhibiting UPF1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense-mediated mRNA decay |
| title_sort | inhibiting upf1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense mediated mrna decay |
| topic | CP: Cancer CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725006904 |
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