What does this research mean for the field?

M2 macrophages promote lymphatic metastasis in triple-negative breast cancer by regulating PKM2 nuclear translocation. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

What question did this study set out to answer?

This research aims to uncover the mechanisms by which M2 macrophages influence lymphatic metastasis in triple-negative breast cancer through PKM2 regulation.

February 27, 2026Open Access

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

Key Points

This research aims to uncover the mechanisms by which M2 macrophages influence lymphatic metastasis in triple-negative breast cancer through PKM2 regulation.
Analyzed the interaction between TNBC cells and M2 macrophages
Investigated the role of TGF-β in PKM2 regulation
Conducted pharmacological inhibition studies on PKM2
Assess clinical correlations of macrophage infiltration and patient outcomes
M2 macrophages increase glycolysis and promote lymphatic metastasis via TGF-β and PKM2
TGF-β upregulates PKM2 expression and phosphorylation, leading to its nuclear translocation
Nuclear p-PKM2 activates expression of lymphatic growth factors VEGFC/D, enhancing metastasis
High M2 infiltration correlates with worse survival outcomes in TNBC patients
Serum analysis shows elevated TGF-β in lymphatic metastasis-positive TNBC patients

Abstract

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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