Lactate-induced activation of tumor-associated fibroblasts and IL-8-mediated macrophage recruitment promote lung cancer progression

Abstract

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.

Graphical abstract

Gu et al. investigated the molecular activation mechanism of CAFs which revealed that lung cancer cells stimulate the secretion of lactate, leading to the upregulation of DESMIN in lung fibroblasts. This upregulation is mediated through the translocation of NUSAP1 into the nucleus, facilitating JUNB-mediated DESMIN transcription in DESMIN-positive CAFs. Consequently, these CAFs secrete interleukin-8 (IL-8), which exerts dual effects on the tumor microenvironment, either attracting tumor-associated macrophages (TAMs) or promoting M2 polarization in macrophages. Both responses contribute to the alterations in the tumor microenvironment, ultimately facilitating lung cancer progression.

Highlights

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  LC cells secrete absorbable lactate, which promotes the activation of CAF via upregulating DESMIN.

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  JUNB elements control DESMIN upregulation by lactate.

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  NUSAP1 nucleus translocation upregulates DESMIN levels in CAF cells.

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  NUSAP1 upregulation mimics lactate loss of DESMIN upregulation and promotes CAF activation.

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  DESMIN  ⁺ CAFs secrete IL-8 to promote TAM activation and infiltration.