Lactylation Drives Triple Negative Breast Cancer Progression
- Breast cancer remains the most commonly diagnosed malignancy among women globally.
- Recent research,published in Cancer Biology & Medicine (DOI: 10.20892/j.issn.2095-3941.2025.0173), has identified a novel process called "lactylation" - the modification of proteins and histones by lactate - as a...
- The accumulation of lactate activates multiple pathways that promote tumor progress.These include:
Lactate: The Emerging Master Regulator in Breast Cancer Progression
Table of Contents
Published August 18, 2025
The Challenge of Breast Cancer, Especially TNBC
Breast cancer remains the most commonly diagnosed malignancy among women globally. Within this landscape, triple-negative breast cancer (TNBC) presents a especially formidable challenge. Characterized by a lack of common therapeutic targets, TNBC ofen exhibits aggressive behavior and a high rate of recurrence.A key factor driving this aggressiveness is the “Warburg effect,” where cancer cells prioritize glucose metabolism into lactate, even in the presence of oxygen. This process creates an acidic environment that promotes metastasis and suppresses the body’s immune defenses.
Unveiling Lactylation: A New Layer of Complexity
Recent research,published in Cancer Biology & Medicine (DOI: 10.20892/j.issn.2095-3941.2025.0173), has identified a novel process called “lactylation” - the modification of proteins and histones by lactate – as a critical driver of tumor progression. researchers from Nanjing Medical University and Zhejiang University systematically reviewed over 120 studies to reveal how this epigenetic modification alters protein function within both cancer cells and the surrounding immune environment.
How Lactate Fuels Tumor Growth
The accumulation of lactate activates multiple pathways that promote tumor progress.These include:
- Invasion: Acidification of the tumor microenvironment enhances invasion through the activation of matrix metalloproteinases.
- Immunosuppression: Lactate induces immunosuppression by upregulating PD-L1 and polarizing macrophages towards an M2 phenotype.
- Angiogenesis: Lactate stimulates the formation of new blood vessels (angiogenesis) via VEGF signaling.
Furthermore,lactylation directly modifies histones (like H3K18la and H4K12la) and crucial tumor suppressor proteins,such as p53,with the AARS1 enzyme playing a central role in this process.
The “Double-Hit” Effect in TNBC
In TNBC, lactylation appears to have a particularly devastating effect, concurrently silencing tumor suppressor genes and activating oncogenic pathways. This “double-hit” mechanism explains, in part, the poor prognosis associated with this subtype. Clinical data reveals that patients exhibiting high levels of lactylation markers experience a 3.5-fold increase in mortality rates.
Promising Therapeutic Strategies
Researchers are exploring several avenues for therapeutic intervention. In preclinical studies, a combination therapy utilizing nanoparticle-delivered lactate oxidase (to reduce lactate levels) alongside PD-L1 siRNA (to boost immune response) resulted in a 68% reduction in tumor size in mouse models. This suggests a powerful synergistic effect when addressing both metabolic and immune evasion strategies.
beyond this, pharmaceutical companies are actively investigating small molecules designed to inhibit AARS1-mediated lactylation, offering a potential direct approach to disrupting this process.
new Diagnostic Horizons
The research team has developed a 24-gene lactate metabolism signature capable of accurately predicting a patient’s response to treatment. Importantly, they found a strong correlation between lactate levels detected through non-invasive MRI and the aggressiveness of HER2-positive tumors, suggesting that lactate levels could serve as a valuable biomarker for monitoring disease progression.
future Directions & Clinical Opportunities
The findings highlight three immediate clinical opportunities:
- Drug Repurposing: Investigating the use of existing metabolic drugs, such as lactate dehydrogenase (LDH) inhibitors, in combination with standard therapies.
- Precision Imaging: Developing PET tracers specifically designed to detect lactylation, enabling more precise tumor imaging and monitoring.
- Early Detection: creating lactylation-based liquid biopsies for the early detection of recurrence.