2. Academic Validation
  3. UFMylation: A supervisor of the HIF1α pathway and a potential therapeutic target for anti-PD-1 combination therapy in hypoxic tumors

UFMylation: A supervisor of the HIF1α pathway and a potential therapeutic target for anti-PD-1 combination therapy in hypoxic tumors

  • Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2500562122. doi: 10.1073/pnas.2500562122.
Yongkang Zou # 1,  Zhaoxiang Wang # 2,  Qiang Jiang # 3 4,  Xia Kong 2,  Xiaohe Ma 5,  Zhengyan Liang 2,  Zhiguo Wang 5,  Beiying Chen 5,  Jiao Yuan 6,  Jiayue Wen 6,  Sheng Ye 1,  Yubin Yan 2,  Binbin Li 2,  Xing-Dong Xiong 2,  Xin-Guang Liu 2,  Zhiwei He 2,  Yafei Cai 3,  Junzhi Zhou 2
Affiliations

Affiliations

  • 1 Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
  • 2 Department of Pathophysiology, School of Basic Medicine, Key Laboratory for Epigenetics of Dongguan City, Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China.
  • 3 Department of Animal Genetics, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
  • 4 Key laboratory of Livestock and Poultry Multi-omics, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Ji'nan 250100, China.
  • 5 Department of Cell Biology, School of Basic Medicine, Hangzhou Normal University, Hangzhou 311121, China.
  • 6 Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health Joint School of Life Sciences, The Guangdong-Hong Kong-Macao Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou 510005, China.
  • # Contributed equally.
PMID: 40601633 DOI: 10.1073/pnas.2500562122
Abstract

Activation of hypoxia signaling has been identified as an innate resistance signature against anti-PD-1 therapy, suggesting its potential as a target for combination treatments. Here, we demonstrate that UFMylation modification of HIF1α stabilizes the protein by antagonizing its ubiquitination and proteasomal degradation under hypoxic conditions. Mechanistically, depletion of UFL1 or defective UFMylation increases HIF1α binding to p53, promoting its degradation. Depletion of UFL1 or UBA5, or defective UFMylation of HIF1α, destabilizes HIF1α, significantly inhibiting tumor growth and development in vitro and in xenograft mouse models. Defective UFMylation of HIF1α enhances the response to anti-PD-1 therapy in xenograft models. Clinically, UBA5 expression is upregulated in breast Cancer tissues, and a selective UBA5 inhibitor reduces UFMylation activity and HIF1α protein levels, thereby enhancing anti-PD-1 combination therapy in mouse tumor models. Our findings highlight UFMylation as a critical posttranslational modification for the HIF1α pathway and a promising therapeutic target in hypoxic tumors.

Keywords

UFMylation; hypoxia; posttranslational modification; tumor microenvironment.

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