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

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

  • Cell Death Dis. 2025 Aug 25;16(1):642. doi: 10.1038/s41419-025-07974-6.
Qinglin Wang # 1 2,  Yuxiang Sun # 1 2,  Jianyu Li # 1 2,  Zhizong Li # 3,  Fangwei Yuan # 1 2,  Zhijun Xia 1 2,  Fanchen Meng 1 2,  Ziyang Shen 1 2,  Yiyang Shen 1 2,  Lin Xu 1 2,  Jie Wang 4 5,  Xi Chen 6 7,  Tongyan Liu 8 9,  Rong Yin 10 11 12
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, 210009, China.
  • 2 Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, 210009, China.
  • 3 The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China.
  • 4 Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, 210009, China. wangjie5204007@hotmail.com.
  • 5 Jiangsu Biobank of Clinical Resources, Nanjing, 210009, China. wangjie5204007@hotmail.com.
  • 6 The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, 213003, China. xichen@nju.edu.cn.
  • 7 Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, 210023, China. xichen@nju.edu.cn.
  • 8 Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, 210009, China. liutongyan@njmu.edu.cn.
  • 9 Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, 210009, China. liutongyan@njmu.edu.cn.
  • 10 Department of Thoracic Surgery, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, 210009, China. rong_yin@njmu.edu.cn.
  • 11 Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, 210009, China. rong_yin@njmu.edu.cn.
  • 12 Collaborative Innovation Center for Cancer Personalized Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, 211116, Nanjing, PR China. rong_yin@njmu.edu.cn.
  • # Contributed equally.
PMID: 40855046 DOI: 10.1038/s41419-025-07974-6
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.

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