Lactate-driven metabolic-epigenetic reprogramming in breast cancer: immune evasion and therapeutic resistance.
4 affiliations
- 1Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, 610041, China.
- 2Department of General Internal Medicine, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, No. 55, Section 4, Renmin South Road, Wuhou District, Chengdu, 610041, China.
- 3Department of General Internal Medicine, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, No. 55, Section 4, Renmin South Road, Wuhou District, Chengdu, 610041, China. [email protected].
- 4Department of Breast, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, No. 55, Section 4, Renmin South Road, Wuhou District, Chengdu, 610041, China. [email protected].
Abstract
Background
Breast cancer develops within a metabolically heterogeneous tumor microenvironment characterized by regional hypoxia, glycolytic activation, lactate accumulation, extracellular acidification, and impaired antitumor immunity. Lactate is now recognized not only as a metabolic end product, but also as a transported substrate, a receptor ligand, and a potential source of lysine lactylation.Main body
In this Review, we summarize current evidence on lactate production, MCT1/MCT4-dependent trafficking, GPR81/HCAR1-mediated sensing, immune remodeling, and metabolic-epigenetic regulation in breast cancer. We organize these effects into three interconnected layers. First, extracellular acidification, nutrient competition, and redox stress produce rapid and potentially reversible suppression of CD8⁺ T cells, natural killer cells, and dendritic cells. Second, sustained lactate-rich conditions alter the relative fitness of immune and stromal populations, weakening cytotoxic effectors while supporting regulatory T cells, tumor-associated macrophages, suppressive myeloid populations, and stromal immune exclusion. Third, histone and non-histone lactylation, together with RNA-level and chromatin regulatory mechanisms, may contribute to more durable state fixation. We distinguish direct breast cancer evidence from mechanisms established in other cancers and from transcriptome-based lactylation-associated signatures. We also discuss methodological limitations, subtype-specific evidence, and therapeutic strategies targeting lactate production, transport, sensing, and downstream epigenetic regulation.Short conclusion
Lactate-driven metabolic and epigenetic regulation provides a useful framework for understanding immune evasion and therapeutic resistance in breast cancer. However, direct mechanistic evidence remains concentrated in triple-negative breast cancer and tumor-intrinsic phenotypes. Lactylation should therefore be considered a candidate mechanism of durable state fixation rather than a universal explanation for lactate-associated effects. Future studies integrating direct lactylation measurements, spatial multi-omics, functional perturbation, and patient-derived models will be required to define clinically actionable lactate-dependent states.
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BibTeX
@article{sun2026lactatedriven,
title = {{Lactate-driven metabolic-epigenetic reprogramming in breast cancer: immune evasion and therapeutic resistance.}},
author = {Lei Sun and Li Wang and Wanqin Zeng and Shiyan Zeng},
journal = {Clinical epigenetics},
year = {2026},
month = jul,
doi = {10.1186/s13148-026-02216-8},
url = {https://europepmc.org/article/MED/42907906},
note = {CC BY},
}
RIS
TY - JOUR
TI - Lactate-driven metabolic-epigenetic reprogramming in breast cancer: immune evasion and therapeutic resistance.
AU - Lei Sun
AU - Li Wang
AU - Wanqin Zeng
AU - Shiyan Zeng
PY - 2026
DA - 2026/07/01
JO - Clinical epigenetics
DO - 10.1186/s13148-026-02216-8
UR - https://europepmc.org/article/MED/42907906
AB - Background Breast cancer develops within a metabolically heterogeneous tumor microenvironment characterized by regional hypoxia, glycolytic activation, lactate accumulation, extracellular acidification, and impaired antitumor immunity. Lactate is now recognized not only as a metabolic end product, but also as a transported substrate, a receptor ligand, and a potential source of lysine lactylation.Main body In this Review, we summarize current evidence on lactate production, MCT1/MCT4-dependent trafficking, GPR81/HCAR1-mediated sensing, immune remodeling, and metabolic-epigenetic regulation in breast cancer. We organize these effects into three interconnected layers. First, extracellular acidification, nutrient competition, and redox stress produce rapid and potentially reversible suppression of CD8⁺ T cells, natural killer cells, and dendritic cells. Second, sustained lactate-rich conditions alter the relative fitness of immune and stromal populations, weakening cytotoxic effectors while supporting regulatory T cells, tumor-associated macrophages, suppressive myeloid populations, and stromal immune exclusion. Third, histone and non-histone lactylation, together with RNA-level and chromatin regulatory mechanisms, may contribute to more durable state fixation. We distinguish direct breast cancer evidence from mechanisms established in other cancers and from transcriptome-based lactylation-associated signatures. We also discuss methodological limitations, subtype-specific evidence, and therapeutic strategies targeting lactate production, transport, sensing, and downstream epigenetic regulation.Short conclusion Lactate-driven metabolic and epigenetic regulation provides a useful framework for understanding immune evasion and therapeutic resistance in breast cancer. However, direct mechanistic evidence remains concentrated in triple-negative breast cancer and tumor-intrinsic phenotypes. Lactylation should therefore be considered a candidate mechanism of durable state fixation rather than a universal explanation for lactate-associated effects. Future studies integrating direct lactylation measurements, spatial multi-omics, functional perturbation, and patient-derived models will be required to define clinically actionable lactate-dependent states.
SN - 1868-7083
ER -