2. Academic Validation
  3. Targeting the UFL1-PARP1 axis amplifies anti-tumor immunity

Targeting the UFL1-PARP1 axis amplifies anti-tumor immunity

  • Cell Rep. 2025 Oct 28;44(10):116433. doi: 10.1016/j.celrep.2025.116433.
Wenjing Song 1,  Chuan He 2,  Xixin Xing 2,  Gaoshan Xu 2,  Yingmeng Yao 2,  Haiou Li 3,  Yishuang Sun 2,  Wenjun Xiong 2,  Yang Shi 4,  Dilinigeer Tayier 4,  Kechun Yu 2,  Xue Zhang 2,  Zuosong Xie 2,  Yufeng Yuan 5,  Zhiyong Yang 6,  Jinfang Zhang 7
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430071, China; Department of Breast Center, The Second Hospital of Shandong University, Jinan 250033, China.
  • 2 Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 3 Department of Dermatology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
  • 4 Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430071, China.
  • 5 Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430071, China; State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: yuanyf1971@whu.edu.cn.
  • 6 Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430071, China. Electronic address: yangzhiyong@whu.edu.cn.
  • 7 Department of Hepatobiliary and Pancreatic Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; State Key Laboratory of Metabolism and Regulation in Complex Organisms, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Hubei Key Laboratory of Tumor Biological Behavior, Hubei Provincial Clinical Research Center for Cancer, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China. Electronic address: jinfang_zhang@whu.edu.cn.
PMID: 41105513 DOI: 10.1016/j.celrep.2025.116433
Abstract

Cancer immunotherapies are widely used to treat various cancers but are largely ineffective against pancreatic ductal adenocarcinoma (PDAC), with the underlying mechanisms poorly understood. UFMylation, a ubiquitin-like modification, regulates diverse biological and pathological processes, yet its role in PDAC remains unclear. This study reports that UFMylation drives PDAC growth and resistance to Cancer Immunotherapy. Mechanistically, the E3 Ligase UFL1 facilitates PARP1 UFMylation, preventing its ubiquitination and degradation. Stabilized PARP1 enhances DNA damage repair, suppresses R-loop formation, and inhibits cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) activation, thereby promoting tumor immune evasion. In contrast, inhibiting UFMylation reverses these effects, facilitating tumor infiltration of cytotoxic CD8+ T cells and improving the efficacy of anti-PD-1 immunotherapy in the pancreatic tumor model. Clinically, UFL1 protein levels are positively correlated with PARP1 and inversely correlated with cGAS-STING activation and CD8+ T cell infiltration in PDAC. These findings highlight UFMylation as a promising therapeutic target to enhance immunotherapy in PDAC.

Keywords

CP: Cancer; CP: Immunology; DNA damage; PARP1; R-loop; UFL1; UFMylation; cGAS-STING; cancer immunotherapy.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z