Hypoxia-induced tumor cell-intrinsic PLAU activation drives immunotherapy resistance in collagenic lung adenocarcinoma

作者：Li Wan, Tonghui Ma, Boye Li, Xiaoming Shi, Shuwen Chen, Xiaoli Sun, Haiyan Ge, Cheng Lu, Weiyong Yu, Ning Zhou, Yue Xu, Li Ma, Zhaoxia Wang · 发表于：International Immunopharmacology · 年份：2025 · DOI：10.1016/j.intimp.2025.115161 · 被引用次数：5 · 研究领域：Cancer, Hypoxia, and Metabolism、Hippo pathway signaling and YAP/TAZ、Autophagy in Disease and Therapy

Background Hypoxia, as one of the hallmarks in the progression of solid tumors, has been established as critically important for tumor adaptive survival; however, its role in mediating tumor microenvironment remodeling in advanced lung adenocarcinoma (LUAD) remains incompletely defined. Methods Bioinformatics methods were conducted to establish a “hypoxia gene module” and perform molecular subtyping of advanced LUAD patients.Western blotting and immunohistochemistry analyses were performed to elucidate the role of PLAU-PLAUR (also known as uPA-uPAR) signaling activation in hypoxia-associated “Collagenic” LUAD development. Primary pulmonary fibroblasts were isolated, and a co-culture system was established for further investigation. QRT-PCR, Western blotting, and ELISA assays were employed to assess PLAU-PLAUR pathway involvement in CAFs activation. Additionally, CUT&RUN, mass spectrometry, immunofluorescence, and co-immunoprecipitation experiments were conducted to explore the molecular mechanisms of HIF1A-induced PLAU upregulation. In vivo studies were undertaken to examine PLAU-PLAUR activation's impact on the formation of a collagen-rich tumor microenvironment. Results We observed that advanced LUAD patients with high hypoxia exhibited higher fibrosis and increased infiltration of immunosuppressive cells in their microenvironment. Screening intercellular communication signals revealed abnormal activation of the PLAU-PLAUR pathway between tumor cells and fibroblasts in hypo...