Fan Hongjie, Zhao Huzi, Gao Lili, Dong Yucheng, Zhang Pei, Yu Pengfei, Ji Yunfei, Chen Zhe-Sheng, Liang Xinmiao, Chen Yang
State Key Laboratory of Phytochemistry and Natural Medicines, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
Ganjiang Chinese Medicine Innovation Center, Nanchang, 330000, China.
Adv Sci (Weinh). 2025 Jun;12(23):e2500589. doi: 10.1002/advs.202500589. Epub 2025 Apr 27.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, immunosuppressive tumor microenvironment (TME) that limits therapeutic efficacy. This study investigates the role of cellular communication network factor 1 (CCN1, also known as Cyr61), an extracellular matrix-associated protein, in modulating the TME of PDAC. It is demonstrated that Ccn1 promotes PDAC progression by upregulating collagen and chemokine expression, thereby facilitating immune cell exclusion and enhancing tumor growth. Using a Ccn1-deficient PDAC model, decreased collagen and chemokine levels are observed, resulting in increased infiltration of cytotoxic immune cells and reduced myeloid-derived suppressor cells (MDSCs). Furthermore, Ccn1-deficient tumors exhibit heightened sensitivity to gemcitabine and show enhanced responsiveness to anti-programmed cell death 1 (anti-PD1) therapy. Mechanistically, Ccn1 regulates chemokine production through collagen expression, with chemokine levels remaining suppressed even upon interferon-gamma treatment in collagen-deficient cells. These findings highlight Ccn1 as a potential therapeutic target that reprograms the TME to enhance the efficacy of both chemotherapy and immunotherapy in PDAC, providing a novel approach for overcoming immune resistance in PDAC.
胰腺导管腺癌（PDAC）的特征是存在致密的免疫抑制性肿瘤微环境（TME），这限制了治疗效果。本研究调查了细胞通讯网络因子1（CCN1，也称为Cyr61），一种细胞外基质相关蛋白，在调节PDAC的TME中的作用。结果表明，Ccn1通过上调胶原蛋白和趋化因子的表达促进PDAC进展，从而促进免疫细胞排斥并增强肿瘤生长。使用Ccn1缺陷型PDAC模型，观察到胶原蛋白和趋化因子水平降低，导致细胞毒性免疫细胞浸润增加，髓源性抑制细胞（MDSC）减少。此外，Ccn1缺陷型肿瘤对吉西他滨表现出更高的敏感性，并且对抗程序性细胞死亡1（抗PD1）疗法表现出更强的反应性。从机制上讲，Ccn1通过胶原蛋白表达调节趋化因子的产生，在胶原蛋白缺陷型细胞中，即使在干扰素-γ处理后，趋化因子水平仍受到抑制。这些发现突出了Ccn1作为一个潜在的治疗靶点，它可以重新编程TME，以增强PDAC化疗和免疫治疗的疗效，为克服PDAC的免疫抗性提供了一种新方法。
