# Lactate transmission from hypoxic tumor cells promotes macrophage senescence and M2 polarization via the DNMT1-NHE7 axis to accelerate endometrial cancer progression

## TL;DR

This study shows how lactate from hypoxic tumor cells promotes cancer growth by causing macrophage changes through a specific molecular pathway.

## Contribution

The study identifies a novel DNMT1-NHE7 axis linking lactate transmission to macrophage senescence and M2 polarization in endometrial cancer.

## Key findings

- HIF1A drives lactate production in EC cells, which is transported to macrophages via MCT1.
- Lactate induces DNMT1 lactylation, leading to NHE7 downregulation and M2 macrophage polarization.
- NHE7 overexpression in macrophages reduces tumor growth and M2 polarization in xenograft models.

## Abstract

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.