Triple-negative breast cancer (TNBC) is highly aggressive, difficult to treat and commonly develops visceral metastasis, including lung metastasis. We observed that High mobility group box 1 protein (HMGB1) was highly expressed in human TNBC and positively correlated with cancer metastasis. The hypoxic tumor environment is known to regulate HMGB1 secretion, but an understanding of the underlying mechanism by which tumor-derived HMGB1 regulates interstitial components and promotes breast cancer lung metastasis has remained elusive. The results of the present study showed that the number of CD62L^dim neutrophils, which have a strong ability to produce neutrophil extracellular traps (NETs), increased significantly in both peripheral blood and lung tissues in a mouse TNBC model and were regulated by tumor-derived HMGB1 through the TLR2 pathway. Furthermore, serum HMGB1 levels were positively correlated with CD62L^dim neutrophils in 86 breast cancer patients. We demonstrated that CD62L^dim neutrophils accelerated lung metastasis and that interventions targeting the “HMGB1-CD62L^dim neutrophil-NETs” axis could inhibit lung metastasis. Our results suggest that the combination of HMGB1 and CD62L^dim neutrophils is a potential marker for breast cancer lung metastasis and is novel target for future prevention and therapy.

三阴性乳腺癌 (TNBC) 具有高度侵袭性，难以治疗，并且通常会发生内脏转移，包括肺转移。我们观察到高迁移率族框 1 蛋白 (HMGB1) 在人类 TNBC 中高表达，并且与癌症转移呈正相关。已知缺氧肿瘤环境调节 HMGB1 分泌，但对肿瘤来源的 HMGB1 调节间质成分和促进乳腺癌肺转移的潜在机制的理解仍然难以捉摸。本研究的结果表明，CD62L的数量^暗淡中性粒细胞具有很强的产生中性粒细胞胞外陷阱（NETs）的能力，在小鼠 TNBC 模型的外周血和肺组织中显着增加，并通过 TLR2 途径受肿瘤来源的 HMGB1 调节。此外，在 86 名乳腺癌患者中，血清 HMGB1 水平与 CD62L^暗淡中性粒细胞呈正相关。我们证明 CD62L^暗中性粒细胞加速肺转移，针对“HMGB1-CD62L^暗中性粒细胞-NETs”轴的干预措施可以抑制肺转移。我们的结果表明 HMGB1 和 CD62L^暗中性粒细胞的组合是乳腺癌肺转移的潜在标志物，是未来预防和治疗的新靶点。