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

  • Cell Death Dis. 2026 Feb 25;17(1):262. doi: 10.1038/s41419-026-08524-4.
Yuqin Yang  #  1 ,  Honghui Ye  #  1 ,  Di Zhong  #  1 ,  Jian Gao  #  1 ,  Miao Yu  2 ,  Lei Chen  1 ,  Ruoshi Zhou  1 ,  Liguo Zhang  1 ,  Yunyan Cong  1 ,  Zhen Qiao  3 ,  Lixin Guan  4 ,  Yinyan Mao  1 ,  Zhiping Li  1 ,  Wenjing Tian  5 ,  Bin Zhao  6 ,  Hong Zhao  7
Affiliations
  • 1. The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China.
  • 2. Jilin People's Hospital, Jijin, China.
  • 3. Zhuhai Maternity and Child Health Hospital, Zhuhai, China.
  • 4. Shenzhen Second People's Hospital, Shenzhen, China.
  • 5. The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China. [email protected].
  • 6. Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, China. [email protected].
  • 7. The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China. [email protected].
  • # Contributed equally.
PMID: 41741407 DOI: 10.1038/s41419-026-08524-4
Abstract

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.

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