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

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.