# Histone lactylation-derived TET2 enhanced Arg1-mediated MDSC immunosuppression

## TL;DR

This study shows how lactate in tumors boosts immune suppression by changing histone lactylation and TET2, offering a new cancer treatment target.

## Contribution

The study reveals a novel mechanism where histone lactylation enhances MDSC immunosuppression via TET2 and ARG1 upregulation.

## Key findings

- Lactate-induced histone lactylation increases TET2 expression in MDSCs.
- TET2 modulates ARG1 promoter methylation through STAT3, enhancing immunosuppression.
- This mechanism presents a new therapeutic target for cancer treatment.

## Abstract

In the tumor microenvironment (TME), tumor cells secrete a large amounts of lactate due to the “Warburg effect”, which plays a significant role in regulating gene transcription. Recently, the role of lactate in gene transcription has been increasingly understood. Myeloid-derived suppressor cells (MDSCs) are inhibitory cells of bone marrow origin that possess marked abilities to suppress immune cell responses. Within the TME, MDSCs inhibit T cell-mediated specific anti-tumor immunity, as well as non-specific anti-tumor immunity mediated by NK cells and macrophages, by expressing high levels of Arg1, iNOS, and ROS.

This study used the Lewis lung carcinoma cell line to establish a lung cancer xenograft model; MDSCs were isolated from the spleens of these mice for subsequent experiments. Protein expression was analyzed by Western blotting, mRNA expression by qRT-PCR, protein-DNA interactions by ChIP-qPCR, and DNA methylation by MSP-qPCR.

This research shows that histone lactylation enhances the immunosuppressive function of MDSCs. Mechanistically, lactate-induced histone lactylation upregulates TET2, which, using STAT3 as a bridge, modulates ARG1 promoter methylation to upregulate its expression and ultimately enhance the immunosuppressive function of MDSCs.

This research reveals that the histone lactylation-mediated alteration of TET2 presents a novel therapeutic target for cancer treatment.