2. Academic Validation
  3. Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusion

Intrapleural dual blockade of IL-6 and PD-L1 reprograms CAF dynamics and the tumor microenvironment in lung cancer-associated malignant pleural effusion

  • Respir Res. 2025 May 10;26(1):180. doi: 10.1186/s12931-025-03263-0.
Qinpei Cheng # 1,  Xueying Zuo # 1,  Zimu Wang 1 2,  Wanjun Lu 1,  Yuxin Jiang 3,  Jiaxin Liu 1 2,  Xinying Li 1 2,  Qiuli Xu 3,  Suhua Zhu 1,  Xin Liu 1,  Yong Song 4 5,  Ping Zhan 6,  Tangfeng Lv 7 8
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 2 Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 3 Department of Respiratory and Critical Care Medicine, School of Medicine, Affiliated Jinling Hospital, Southeast University, Nanjing, China.
  • 4 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. yong.song@nju.edu.cn.
  • 5 Department of Respiratory and Critical Care Medicine, School of Medicine, Affiliated Jinling Hospital, Southeast University, Nanjing, China. yong.song@nju.edu.cn.
  • 6 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. zhanping207@163.com.
  • 7 Department of Respiratory and Critical Care Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. TangfengLv7210@nju.edu.cn.
  • 8 Department of Respiratory and Critical Care Medicine, School of Medicine, Affiliated Jinling Hospital, Southeast University, Nanjing, China. TangfengLv7210@nju.edu.cn.
  • # Contributed equally.
PMID: 40349069 DOI: 10.1186/s12931-025-03263-0
Abstract

Background: Malignant pleural effusion (MPE) is a severe complication in lung Cancer, characterized by an immunosuppressive tumor microenvironment (TME) and limited therapeutic options. This study investigates the role of IL-6 in regulating immune suppression and tumor progression in MPE and evaluates the efficacy of dual IL-6 and PD-L1 blockade.

Methods: IL-6 levels were measured in MPE and paired serum samples from lung Cancer patients, and correlations with PD-L1 expression and clinical outcomes were analyzed using publicly available datasets. RNA Sequencing and immune deconvolution were used to assess immune cell infiltration. CAFs and immune cell infiltration were further evaluated using flow cytometry, immunohistochemistry, and multiplex immunofluorescence. In vitro co-culture systems were employed to simulate the MPE microenvironment and explore IL-6 interactions with CAFs, as well as its regulatory effect on tumor cell PD-L1 expression.

Results: IL-6 levels were significantly elevated in MPE compared to paired serum and correlated with higher PD-L1 expression and poor survival outcomes in lung Cancer patients. In the MPE mouse model, combination therapy with IL-6 and PD-L1 blockade reduced MPE volume, tumor burden, and PD-L1 expression, while enhancing T cell infiltration and alleviating TME immunosuppression. IL-6 was found to drive a positive feedback loop with iCAFs, promoting an immunosuppressive environment. In vitro, IL-6 from the MPE upregulated tumor cell PD-L1 expression the IL-6/STAT3 pathway.

Conclusion: This study identifies IL-6 as a critical contributor of immune suppression and tumor progression in MPE. The combination of IL-6 and PD-L1 blockade effectively alleviated immunosuppression and reduced tumor burden, offering a potential therapeutic approach for MPE management.

Keywords

Cancer-associated fibroblast; IL-6; Immunotherapy; Lung cancer; Malignant pleural effusion; PD-L1.

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