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.

中文翻译：

---

乳酸诱导的肿瘤相关成纤维细胞激活和 IL-8 介导的巨噬细胞募集促进肺癌进展


肿瘤微环境的改变与肿瘤细胞的代谢表型密切相关。癌症相关成纤维细胞（CAF）在肿瘤生长和转移中发挥着关键作用。现有研究表明，肿瘤细胞产生的乳酸可以激活 CAF，但其确切的潜在机制在很大程度上仍未被探索。在本研究中，我们最初发现肺癌细胞来源的乳酸可以促进NUSAP1的核转位，随后导致转录复合物JUNB-FRA1-FRA2在DESMIN启动子附近募集并促进DESMIN转录激活，从而促进CAF的激活。此外，DESMIN阳性的CAF反过来会分泌IL-8，招募TAM或促进巨噬细胞的M2极化，进一步促进肿瘤微环境的改变并促进肺癌进展。此外，我们观察到使用 IL-8 受体拮抗剂 SB225002 或 Navarixin 显着减少 TAM 浸润并增强抗 PD-1 或​​抗 PD-L1 治疗的疗效。这一发现表明，抑制IL-8R活性可以减弱CAF对肿瘤微环境的影响，从而抑制肺癌的进展。