# Lactate metabolism and protein lactylation in cancer

## TL;DR

Lactate metabolism and lactylation influence cancer growth and immune evasion, offering new therapeutic targets.

## Contribution

This review synthesizes current knowledge on lactylation's role in cancer and highlights its therapeutic potential.

## Key findings

- Lactylation modulates cancer cell proliferation and immune evasion via multiple cell types in the tumor microenvironment.
- Targeting lactylation pathways enhances the effectiveness of existing cancer therapies like immune checkpoint inhibitors.
- Preclinical evidence suggests lactylation inhibition could improve CAR-T therapy and chemotherapy outcomes.

## Abstract

Lactylation is a recently identified post-translational modification that links cellular metabolism to gene regulation, playing pivotal roles in cancer development and the tumor microenvironment (TME). Derived from lactate produced by glycolysis and glutamine metabolism, lactylation occurs on both histone and non-histone proteins, modulating transcription, protein function, and cellular signaling. In tumors, lactylation contributes to proliferation, metastasis, therapy resistance, and immune evasion by influencing the function of Treg cells, macrophages, dendritic cells, and NK cells. Its dynamic regulation by “writers” (e.g., p300), “erasers” (e.g., Histone deacetylases (HDACs), Sirtuins3 (SIRT3)), and transporters (e.g., monocarboxylate transporters (MCT) 1/4) provides multiple intervention points for therapy. Preclinical studies demonstrate that targeting lactylation directly or indirectly—through LDH (lactate dehydrogenase) inhibition, MCT blockade, or modulation of lactyltransferases—enhances the efficacy of immune checkpoint inhibitors, Chimeric Antigen Receptor T (CAR-T) therapy, and chemotherapeutic agents.Despite these advances, critical questions remain regarding the specificity of lactylation compared with other post-translational modifications, the tumor types most dependent on lactylation, and reliable biomarkers to guide treatment. Additionally, clinical validation of lactylation-targeting strategies is limited. Future research integrating mechanistic studies, patient-derived samples, and multi-omics approaches is essential to elucidate context-dependent functions, refine therapeutic targets, and develop precision interventions.This review provides a comprehensive summary of lactylation biology in cancer, highlighting its metabolic-epigenetic interplay, immunomodulatory roles, and therapeutic potential. By synthesizing current evidence, we aim to guide future studies and clinical strategies targeting lactylation to improve cancer treatment outcomes.