2. Academic Validation
  3. IRE1α translational suppression potentiates STING-dependent chemoresistance in pancreatic cancer

IRE1α translational suppression potentiates STING-dependent chemoresistance in pancreatic cancer

  • Cell Death Dis. 2025 Oct 6;16(1):680. doi: 10.1038/s41419-025-07999-x.
Yuan Luo # 1 2,  Mengqi Sun # 3,  Lei Chang # 3,  Zinan He 4,  Xinghang Zhou 3,  Yaming Yuan 5,  Huijuan Sun 5,  Shiqi Luo 6,  Jinyan Huang 3,  Hongkun Wu 3,  Wenjun Liu 3,  Zhangsen Zhou 5,  Yuanhui Mao 6,  Yewei Ji 7 8,  Tingbo Liang 9
Affiliations

Affiliations

  • 1 Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases & Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. luoyuan715@126.com.
  • 2 Department of Immunology, School of Basic Medical Science & Chongqing Key Laboratory of Tumor Immune Regulation and Immune Intervention, Chongqing Medical University, Chongqing, China. luoyuan715@126.com.
  • 3 Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases & Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) & Department of Infectious Diseases of the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 5 Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
  • 6 Department of Urology of the Second Affiliated Hospital, Liangzhu Laboratory, School of Medicine, Zhejiang University, Hangzhou, China.
  • 7 Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases & Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. ywji@cqmu.edu.cn.
  • 8 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) & Department of Infectious Diseases of the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. ywji@cqmu.edu.cn.
  • 9 Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases & Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. liangtingbo@zju.edu.cn.
  • # Contributed equally.
PMID: 41053142 DOI: 10.1038/s41419-025-07999-x
Abstract

Chemotherapy remains a standard treatment for pancreatic ductal adenocarcinoma (PDAC); however, its effectiveness is limited, and the underlying mechanisms are poorly understood. STING plays diverse and critical roles in Cancer, yet the role of PDAC cell-intrinsic STING signaling and its regulation under chemotherapy remain unclear. Here, we report that chemotherapy induces Cancer cell-intrinsic STING signaling and that STING deletion in PDAC enhances cell death under chemotherapy while suppressing tumor growth in both immune-deficient and immune-competent mice. Interestingly, chemotherapy selectively inhibits translation of IRE1α, an ER membrane protein and a canonical mediator of ER stress. Loss of IRE1α in PDAC amplifies STING signaling and increases resistance to chemotherapy. Mechanistically, IRE1α interacts with STING via their transmembrane regions, reducing STING stability in PDAC cells. Our study reveals that PDAC cells downregulate IRE1α to reinforce STING-mediated pro-survival response; however, this adaptation also makes them more vulnerable to proteostasis imbalance and ER stress-induced cell death. Notably, we demonstrate that combining ER stress inducers with STING signaling inhibition enhances chemotherapy efficacy both in vitro and in vivo.

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