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<p>Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, is characterised by poor prognosis and frequent lymph node metastasis (LNM), a hallmark of disease progression. Crosstalk between TNBC cells and M2-polarized macrophages drives malignant progression, but the specific mechanisms underlying M2 macrophage-mediated LNM in TNBC remain poorly defined. This study revealed that M2 macrophage-derived TGF-β increases glycolysis and lymphatic metastasis in TNBC via a PKM2-centred axis. TGF-β dually regulates PKM2 by transcriptionally upregulating its expression and posttranslational phosphorylation. This dual regulation drives PKM2-mediated metabolic reprogramming to increase tumour glucose uptake while promoting the nuclear translocation of p-PKM2, which transcriptionally activates the lymphatic growth factors VEGFC/D. VEGFC/D subsequently stimulates VEGF-dependent lymphangiogenesis, accelerating metastasis. Pharmacological PKM2 inhibition blocked PKM2 phosphorylation/nuclear translocation and suppressed VEGFC/D expression, thereby attenuating LNM. Clinically, high M2 macrophage infiltration correlated with a shorter disease-free survival and overall survival, paralleling prognostic trends in cohorts stratified by PKM2, VEGFC/D, or lymphatic density levels. Serum analysis in an independent TNBC cohort confirmed elevated TGF-β levels in LNM-positive versus LNM-negative patients. Our findings identify PKM2 as a driver of M2 macrophage-induced VEGFC/D overexpression and lymphatic metastasis, highlighting its therapeutic potential for TNBC patients with high LNM risk.</p>

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M2 macrophages promote lymphatic metastasis by regulating PKM2 nuclear translocation in triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月25日

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  • Yuqin Yang,
  • Honghui Ye,
  • Di Zhong,
  • Jian Gao,
  • Miao Yu,
  • Lei Chen,
  • Ruoshi Zhou,
  • Liguo Zhang,
  • Yunyan Cong,
  • Zhen Qiao,
  • Lixin Guan,
  • Yinyan Mao,
  • Zhiping Li,
  • Wenjing Tian,
  • Bin Zhao,
  • Hong Zhao

摘要

Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, is characterised by poor prognosis and frequent lymph node metastasis (LNM), a hallmark of disease progression. Crosstalk between TNBC cells and M2-polarized macrophages drives malignant progression, but the specific mechanisms underlying M2 macrophage-mediated LNM in TNBC remain poorly defined. This study revealed that M2 macrophage-derived TGF-β increases glycolysis and lymphatic metastasis in TNBC via a PKM2-centred axis. TGF-β dually regulates PKM2 by transcriptionally upregulating its expression and posttranslational phosphorylation. This dual regulation drives PKM2-mediated metabolic reprogramming to increase tumour glucose uptake while promoting the nuclear translocation of p-PKM2, which transcriptionally activates the lymphatic growth factors VEGFC/D. VEGFC/D subsequently stimulates VEGF-dependent lymphangiogenesis, accelerating metastasis. Pharmacological PKM2 inhibition blocked PKM2 phosphorylation/nuclear translocation and suppressed VEGFC/D expression, thereby attenuating LNM. Clinically, high M2 macrophage infiltration correlated with a shorter disease-free survival and overall survival, paralleling prognostic trends in cohorts stratified by PKM2, VEGFC/D, or lymphatic density levels. Serum analysis in an independent TNBC cohort confirmed elevated TGF-β levels in LNM-positive versus LNM-negative patients. Our findings identify PKM2 as a driver of M2 macrophage-induced VEGFC/D overexpression and lymphatic metastasis, highlighting its therapeutic potential for TNBC patients with high LNM risk.