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IRE1α translational suppression potentiates STING-dependent chemoresistance in pancreatic cancer
Yuan Luo1,2, Mengqi Sun3, Lei Chang3
1Zhejiang 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.
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.
Insights
Chemotherapy resistance in pancreatic cancer involves STING signaling. Inhibiting STING and inducing ER stress enhances treatment effectiveness by promoting cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Chemotherapy is a standard treatment for pancreatic ductal adenocarcinoma (PDAC), but its efficacy is limited.
- The mechanisms underlying chemotherapy resistance in PDAC, particularly involving STING signaling within cancer cells, are not well understood.
Purpose of the Study:
- To investigate the role of cancer cell-intrinsic STING signaling in PDAC response to chemotherapy.
- To elucidate the mechanisms by which STING signaling is regulated under chemotherapy and its impact on treatment outcomes.
Main Methods:
- Investigated STING signaling in PDAC cells treated with chemotherapy.
- Utilized STING deletion models in PDAC to assess tumor growth and cell death.
- Examined the role of IRE1α (inositol-requiring enzyme 1 alpha) in regulating STING signaling and chemotherapy response.
- Analyzed the interaction between IRE1α and STING at the molecular level.
- Evaluated the combined effect of ER stress inducers and STING inhibition on chemotherapy efficacy in vitro and in vivo.
Main Results:
- Chemotherapy induces STING signaling within PDAC cells.
- STING deletion in PDAC enhances chemotherapy-induced cell death and suppresses tumor growth.
- Chemotherapy selectively inhibits IRE1α translation, leading to amplified STING signaling and increased chemoresistance.
- IRE1α interacts with STING, reducing its stability; PDAC cells downregulate IRE1α to promote STING-mediated survival.
- Combining ER stress inducers with STING inhibition significantly improves chemotherapy efficacy.
Conclusions:
- PDAC cells exploit the IRE1α-STING axis to resist chemotherapy, but this adaptation creates vulnerabilities to ER stress.
- Targeting STING signaling and inducing ER stress represent a promising therapeutic strategy to overcome chemotherapy resistance in pancreatic cancer.
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