Targeting LINC01711 in FAP+ cancer-associated fibroblasts overcomes lactate-mediated immunosuppression and enhances anti-PD-1 efficacy in lung adenocarcinoma

作者：Qinglin Wang, Yuxiang Sun, Jianyu Li, Zhizong Li, Fangwei Yuan, Zhijun Xia, Fanchen Meng, Ziyang Shen, Yiyang Shen, Lin Xu, Jie Wang, Xi Chen, Tongyan Liu, Rong Yin · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07974-6 · 被引用次数：5 · 研究领域：Nanoplatforms for cancer theranostics、Immune cells in cancer、Cancer Immunotherapy and Biomarkers

Abstract The limited response rate to immune checkpoint inhibitors (ICIs) remains a significant challenge in the treatment of lung adenocarcinoma (LUAD). In our study, we identified a lactate-based chemical barrier surrounding FAP + cancer-associated fibroblasts (CAFs) within the LUAD microenvironment (TME), which may hinder the infiltration and function of CD8 + T cells. Further investigation revealed that FAP + CAFs specifically overexpress LINC01711, which drives lactate production by promoting FGFR1-mediated phosphorylation of lactic dehydrogenase A (LDHA) at the Y10 site and facilitating the formation of active LDHA tetramers. These FAP + CAFs then export lactate into TME via the MCT4 transporter, thereby establishing a chemical barrier and fostering an immunosuppressive TME. Notably, we developed a small extracellular vesicle (sEV)-based in vivo self-assembled siRNA system for in vivo knockdown of LINC01711 and demonstrated its potential to enhance the response rate to ICIs in LUAD. Our findings underscore the pivotal role of FAP + CAFs in driving resistance to ICIs and propose novel therapeutic strategies to overcome this obstacle.