Severe fibrosis is primarily driven by the activation of pancreatic stellate cells (PSCs) and plays a crucial role in the poor prognosis associated with pancreatic ductal adenocarcinoma (PDAC). Understanding the complex interactions between tumor cells and their microenvironment is essential for deciphering the regulatory mechanisms of PSC activation. This study reveals the critical role of tumor-derived interleukin 35 (IL-35) in regulating PSC activation, thereby uncovering a promising therapeutic target for mitigating PDAC progression.This study shows that IL-35 secreted by PDAC cells is a critical mediator of bidirectional communication between PDAC cells and PSCs, exacerbating fibrosis. Specifically, IL-35 upregulates the expression of IGFBP2 and Tsp-1 in PDAC cells, which then activate PSCs through the IGF-1R/phosphoinositide 3-kinase/Akt and transforming growth factor-β signaling pathways, respectively.This continuous activation creates an environment that favors tumor cell proliferation and migration, ultimately promoting accelerated tumor growth. Overall, these findings suggest that IL-35 is a promising therapeutic target, and its blockade can not only inhibit PSC activation and stromal fibrosis but also enhance the efficacy of standard chemotherapy (gemcitabine and gemcitabine/albumin-bound paclitaxel). This provides strong rationale for the clinical development of combination strategies targeting PDAC.

Original link

Tumor-Derived Interleukin 35 Promotes Fibrosis in the Tumor Microenvironment of Pancreatic Cancer by Activating Pancreatic Stellate Cells

Pub Date : 2025-11-14

DOI: 10.1002/advs.202509074

Hui Li,  Huizhi Sun,  Jing Liu,  Yan Wu,  Lin Wei,  Jianming Li,  Yudong Yuan,  Peng Xie,  Chao Xu,  Guolu Luo,  Yuqi Guan,  Yukuan Feng,  Antao Chang,  Jihui Hao,  Chongbiao Huang