| 論文作者 |
Luo, Y; Sun, MQ; Chang, L; He, ZN; Zhou, XH; Yuan, YM; Sun, HJ; Luo, SQ; Huang, JY; Wu, HK; Liu, WJ; Zhou, ZS; Mao, YH; Ji, YW; Liang, TB |
| 摘要 |
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 IRE1 alpha, an ER membrane protein and a canonical mediator of ER stress. Loss of IRE1 alpha in PDAC amplifies STING signaling and increases resistance to chemotherapy. Mechanistically, IRE1 alpha interacts with STING via their transmembrane regions, reducing STING stability in PDAC cells. Our study reveals that PDAC cells downregulate IRE1 alpha 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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