Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression
Xuyu Gu,
Yifei Zhu,
Jincheng Su,
Sheng Wang,
Xiangyu Su,
Xu Ding,
Lei Jiang,
Xiang Fei,
Wentian Zhang
Affiliations
Xuyu Gu
Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
Yifei Zhu
Department of Oncology, Shanghai Medical College of Fudan University, Shanghai 200032, China; Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China
Jincheng Su
School of Medicine, Shihezi University, Shihezi 832002, China
Sheng Wang
Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Xiangyu Su
Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China; School of Medicine, Southeast University, Nanjing 210009, China
Xu Ding
Department of Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China; School of Medicine, Southeast University, Nanjing 210009, China
Lei Jiang
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; Corresponding author.
Xiang Fei
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; Corresponding author.
Wentian Zhang
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China; Corresponding author.
Alterations in the tumor microenvironment are closely associated with the metabolic phenotype of tumor cells. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth and metastasis. Existing studies have suggested that lactate produced by tumor cells can activate CAFs, yet the precise underlying mechanisms remain largely unexplored. In this study, we initially identified that lactate derived from lung cancer cells can promote nuclear translocation of NUSAP1, subsequently leading to the recruitment of the transcriptional complex JUNB-FRA1-FRA2 near the DESMIN promoter and facilitating DESMIN transcriptional activation, thereby promoting CAFs' activation. Moreover, DESMIN-positive CAFs, in turn, secrete IL-8, which recruits TAMs or promotes M2 polarization of macrophages, further contributing to the alterations in the tumor microenvironment and facilitating lung cancer progression. Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer.
