Cell death & diseaseJan 30, 2026

Lactate from low-oxygen tumor cells may cause immune cells to age and shift to a tumor-supporting type, speeding up endometrial cancer growth

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Updated Mar 10, 2026

Abstract

Hypoxia increases lactate production in endometrial cancer cells, facilitating tumor progression through macrophage activation.

Hypoxia leads to elevated levels of lactate in endometrial cancer cells via the activation of specific metabolic pathways.
Lactate produced by cancer cells is transported to macrophages, promoting their polarization towards an M2 phenotype.
The lactate triggers changes in macrophages, including modifications to histones that affect gene expression related to pH regulation.
Downregulation of the NHE7 gene in macrophages is associated with enhanced M2 polarization and cell aging, contributing to cancer progression.
In a xenograft model, macrophages that overexpress NHE7 can counteract the tumor-promoting effects of lactate, reducing tumor growth and M2 polarization.

Simplified

Although hypoxia is a well-known key driver of metabolic reprogramming in endometrial cancer (EC), its role in lactate-mediated macrophage activation remains unclear. This study investigates whether hypoxia-mediated lactate metabolism reprogramming facilitated EC progression via macrophages. Our data demonstrated that hypoxia-inducible factor 1 subunit alpha (HIF1A) drives a lactate-regulated metabolic cascade, elevating glycolytic genes and monocarboxylate transporter 3 (MCT3) in EC cells to produce and export more lactate. This lactate is transported to macrophages by MCT1 to drive M2 macrophage polarization. Mechanistically, lactate induces lactylation of Histone 3 in the promoter of DNA methyltransferase 1 (DNMT1) gene and activates transcription in macrophages, leading to the silencing of NHE7 gene expression, a key regulator of intracellular pH. Critically, NHE7 downregulation drives M2 polarization and senescence through the mitogen-activated protein kinase (MAPK) pathway activation in macrophages, ultimately facilitating EC progression. In vivo, we successfully established a xenograft tumor model using Ishikawa cells, and the data further confirmed that NHE7-overexpressing macrophages effectively abrogate exogenous lactate-accelerated xenograft tumor growth, as well as its M2 polarization and senescence. These findings uncover that hypoxia-mediated lactate production and transmission promote tumor-macrophage crosstalk via the DNMT1-NHE7 axis and EC progression, which offers novel therapeutic targets for EC.

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Lactate from low-oxygen tumor cells may cause immune cells to age and shift to a tumor-supporting type, speeding up endometrial cancer growth

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