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<p>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<sup>+</sup> cancer-associated fibroblasts (CAFs) within the LUAD microenvironment (TME), which may hinder the infiltration and function of CD8<sup>+</sup> T cells. Further investigation revealed that FAP<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> CAFs in driving resistance to ICIs and propose novel therapeutic strategies to overcome this obstacle.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月25日

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  • 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

摘要

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.