2. Academic Validation
  3. Inhibiting UPF1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense-mediated mRNA decay

Inhibiting UPF1 methylation enhances tumor immunotherapy sensitivity by reducing nonsense-mediated mRNA decay

  • Cell Rep. 2025 Jul 22;44(7):115919. doi: 10.1016/j.celrep.2025.115919.
Shengyu Zhu 1,  Yucong Bai 1,  Dongjing Zhang 1,  Changsheng Huang 1,  Xu Qian 2,  Pengcheng Li 1,  Tianci Xie 1,  Qi Wu 1,  Anyi Liu 1,  Tong Zhu 1,  Wangshuo Yang 1,  Xiaowei She 1,  Mao Li 1,  Zejun Rao 1,  Siqi Chen 1,  Lang Liu 1,  Chengxin Yu 1,  Xiang Liu 1,  Guihua Wang 3,  Guangyong Zhang 4,  Junbo Hu 5
Affiliations

Affiliations

  • 1 GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
  • 2 Department of General Surgery, First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China.
  • 3 GI 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. Electronic address: ghwang@tjh.tjmu.edu.cn.
  • 4 Department of General Surgery, First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan 250014, Shandong Province, China. Electronic address: guangyongzhang@hotmail.com.
  • 5 GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China. Electronic address: jbhu@tjh.tjmu.edu.cn.
PMID: 40570371 DOI: 10.1016/j.celrep.2025.115919
Abstract

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.

Keywords

CP: Cancer; CP: Immunology; UPF1; autophagy; cancer immunotherapy; methylation; nonsense-mediated mRNA decay.

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