CREB3L1 facilitates pancreatic tumor progression and reprograms intratumoral tumor-associated macrophages to shape an immunotherapy-resistance microenvironment

作者：Haiyan Xu, Shengbai Xue, Yang Sun, Jingyu Ma, Shumin Li, Yanling Wang, Yanling Wang, Tiebo Mao, Weiyu Ge, Ming Yue, Daiyuan Shentu, Wenxin Lu, Yongchao Wang, Yongchao Wang, Jiong Hu, Jiujie Cui, Xiaofei Zhang, Li Cai, Yu Wang, Yu Wang, Liwei Wang · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-010029 · 被引用次数：17 · 研究领域：Endoplasmic Reticulum Stress and Disease、Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers

Background To date, a growing body of evidence suggests that unfolded protein response (UPR) sensors play a vital role in carcinogenesis. However, it remains unclear whether they are involved in pancreatic ductal adenocarcinoma (PDAC) and how they relate to clinical outcomes. This study aims to investigate the biological function and mechanism of how a novel UPR sensor, CREB3L1 works in PDAC and further evaluate its clinical application prospect. Methods We tested UPR signaling including CREB3L1 in Thapsigargin-treated PDAC cells. Subsequently, we defined CREB3L1 expression and further analyzed its expression with clinical characteristics in PDAC. Then, we established gene-modified cells to determine whether CREB3L1 functions in cell proliferation and migration capacity. Besides, we constructed subcutaneously and orthotopically transplanted mice models to verify their progrowing function and pulmonary metastasis models to prove their proinvasion role. What’s more, RNAseq, qPCR, Western blotting, immunohistochemistry and multicolor flow cytometry experiments were used to explore the mechanism of how CREB3L1 worked in PDAC. Lastly, CREB3L1 expression correlation with PDAC immunotherapy outcome and immune cell signatures were explored in the patients with advanced PDAC who received PD-1 antibody therapy. Results We first confirmed CREB3L1 could be induced by endoplasmic reticulum stressor and found its aberrant activation was associated with poorer overall survival in PDAC patie...