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

Abstract Severe fibrosis, predominantly driven by the activation of pancreatic stellate cells (PSCs), plays a crucial role in the poor prognosis associated with pancreatic ductal adenocarcinoma (PDAC). Understanding the intricate interplay between tumor cells and their microenvironment is essential for deciphering the regulatory mechanisms underlying PSC activation. This study sheds light on the critical role of tumor‐derived interleukin‐35 (IL‐35) in modulating PSC activation, thereby unveiling a promising therapeutic target for mitigating PDAC progression. This study demonstrates that IL‐35, secreted by PDAC cells, serves as a key 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 subsequently activates PSCs through the IGF‐1R/phosphoinositide 3‐kinase/Akt and transforming growth factor beta signaling pathways, respectively. This sequential activation fosters an environment conducive to tumor cell proliferation and migration, ultimately driving accelerated tumor growth. Collectively, these findings indicate that IL‐35 is a promising therapeutic target whose blockade not only suppresses PSC activation and stromal fibrosis, but also enhances the efficacy of standard chemotherapies (gemcitabine and gemcitabine/nab‐paclitaxel). This provides a strong rationale for its clinical development as a combinatorial strategy in PDAC treatment.