image: Interplay between lactate and lactylation in the TME. Lactylation: In the tumor microenvironment (TME), lactate is produced through the “Warburg effect”. AARS1 acts as a lactate sensor that mediates global lysine lactylation in tumor cells. This enzyme binds lactate and catalyzes the conversion of lactate to lactate-AMP in the presence of ATP, and subsequently transfers lactate to the lysine acceptor residue. The p300 enzyme is a histone acetyltransferase that catalyzes the transfer of an acetyl group from acetyl-CoA to lysine residues on histones, thus resulting in histone acetylation, and is considered a “writer” of histone lactylation. Acidic environment: Acidification of the TME decreases integrin binding to the ECM and E-cadherin expression, and activates proteinases such as MMP-9, cathepsin B, and hyaluronidase-2, thus facilitating tumor cell invasion. Lactate also binds GPR81, thereby influencing cAMP and Ca2+ levels. Metabolic reprogramming: As a key metabolite linking glycolysis and oxidative phosphorylation, lactate is notably involved in energy supply and metabolic regulation in tumor cells. Immune evasion: Lactate also modulates M2 tumor-associated macrophages and leads to remodeling of the immunosuppressive tumor microenvironment through the PI3K/Akt pathway, promotes tumorigenesis by altering MOESIN lactylation, and enhances TGF-β signaling in Tregs. Antitumor immunity: Lactate enhances CD8+ T-cell stemness and regulates Foxp3-dependent RNA splicing via CTLA-4, thereby maintaining Treg phenotype and function. Akt, protein kinase; AARS1, alanyl-tRNA synthetase 1; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; cAMP, cyclic adenosine monophosphate; ECM, extracellular matrix; GPR81, G protein-coupled receptor 81; MMP-9, matrix metalloproteinase 9; PI3K, phosphatidylinositol 3-kinase; TGF-β, transforming growth factor-β; Tregs, regulatory T cells.
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Credit: Cancer Biology & Medicine
A new review reveals how lactate and its derivative lactylation process drive breast cancer progression, opening new therapeutic possibilities. The study demonstrates that lactate—a metabolic byproduct—not only energizes tumors but also triggers protein modifications that alter gene expression and enable immune evasion. These mechanisms are especially prominent in aggressive triple-negative breast cancer (TNBC). By synthesizing recent discoveries, the research highlights promising strategies to disrupt cancer’s metabolic reprogramming through targeted interventions against lactate production and lactylation. The findings could lead to more precise treatments that improve survival rates while addressing current challenges like chemotherapy resistance. This metabolic-epigenetic approach may redefine standard care for high-risk patients.
Breast cancer maintains its position as the most prevalent malignancy in women worldwide, with triple-negative breast cancer (TNBC) representing the most treatment-resistant subtype due to limited therapeutic targets and frequent relapse. The “Warburg effect”—where cancer cells preferentially metabolize glucose into lactate even with oxygen present—creates an acidic tumor microenvironment that fosters metastasis and blocks immune responses. The newly discovered lactylation process, where lactate modifies proteins and histones, adds another layer of complexity to cancer biology by directly influencing gene activation patterns. While immunotherapies have advanced treatment options, metabolic adaptations continue to undermine their effectiveness. Given these unresolved challenges, researchers emphasize the critical need to investigate lactate-driven mechanisms to develop next-generation therapies.
Published (DOI: 10.20892/j.issn.2095-3941.2025.0173) in Cancer Biology & Medicine, researchers from Nanjing Medical University and Zhejiang University systematically analyzed over 120 recent studies on lactate metabolism in breast cancer. Their review identifies lactylation—a novel post-translational modification—as a key driver of tumor progression through epigenetic regulation. The team details how lactate-induced modifications alter protein function in both cancer cells and immune components within the tumor microenvironment. By mapping these mechanisms across different molecular subtypes, they propose actionable targets including lactate dehydrogenase inhibitors and lactylation-blocking agents that could overcome current treatment limitations, particularly for TNBC patients.
The study establishes that lactate accumulation activates multiple pro-tumor pathways: (1) Acidifying the microenvironment to promote invasion via matrix metalloproteinases; (2) Inducing immunosuppression through PD-L1 upregulation and M2 macrophage polarization; (3) Stimulating angiogenesis via VEGF signaling. The newly characterized lactylation process modifies both histones (e.g., H3K18la, H4K12la) and critical tumor suppressors like p53, with AARS1 enzyme identified as the primary mediator.
In TNBC, lactylation silences tumor suppressor genes while activating oncogenic pathways, creating a “double-hit” effect. Clinical correlations show patients with high lactylation markers have 3.5x worse survival rates. Therapeutically, nanoparticle-delivered lactate oxidase combined with PD-L1 siRNA demonstrated 68% tumor reduction in mouse models by simultaneously addressing metabolic and immune evasion mechanisms.
Diagnostically, the team developed a 24-gene lactate metabolism signature that accurately predicts treatment response. Notably, lactate levels detected via non-invasive MRI correlated strongly with HER2-positive tumor aggressiveness, suggesting potential as a monitoring biomarker. These findings position lactate-lowering strategies as viable adjuvants to existing therapies.
“Lactate is no longer just a waste product—it’s a master regulator of cancer progression,” explains corresponding author Dr. Jian Wu. “Our work reveals how lactylation creates a permissive environment for tumors by simultaneously modifying cancer cell behavior and disabling immune surveillance. The clinical implications are profound: targeting these pathways could benefit the 15%-20% of breast cancer patients with TNBC who currently lack effective options. We’re now collaborating to translate these findings into phase I trials of lactylation inhibitors.”
The research suggests three immediate clinical opportunities: (1) Repurposing existing metabolic drugs like LDH inhibitors for combination therapies; (2) Developing lactylation-specific PET tracers for precision imaging; (3) Creating lactylation-based liquid biopsies for early recurrence detection. Pharmaceutical companies are already exploring small molecules targeting AARS1-mediated lactylation.
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References
DOI
10.20892/j.issn.2095-3941.2025.0173
Original Source URL
Funding information
This work was supported by grants from the National Natural Science Foundation of China (Grant No. 82302626), Gusu Health Talent Project of Suzhou, China (Grant No. GSWS2022076), and Suzhou Key Laboratory of Intelligent Critical Illness Biomarkers Translational Research Project (Grant No. SZS2024029).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 8.4, 5-year IF 6.7), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).
Journal
Cancer Biology & Medicine
DOI
10.20892/j.issn.2095-3941.2025.0173
Subject of Research
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Article Title
Lactate and lactylation in breast cancer: current understanding and therapeutic opportunities
Article Publication Date
16-Jul-2025
COI Statement
The authors declare that they have no competing interests
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Ying Li
Cancer Biology & Medicine
Journal
Cancer Biology & Medicine
DOI
10.20892/j.issn.2095-3941.2025.0173
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Cancer Biology & Medicine
DOI
10.20892/j.issn.2095-3941.2025.0173
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Article Title
Lactate and lactylation in breast cancer: current understanding and therapeutic opportunities
Article Publication Date
16-Jul-2025
COI Statement
The authors declare that they have no competing interests
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/Health and medicine/Diseases and disorders/Cancer/Breast cancer
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Tags: AARS1 lactate sensor roleacidic tumor microenvironment effectsCD8+ T-cell stemness and lactatehistone acetylation and lactylationimmune evasion mechanisms in cancerlactate in breast cancerlactate’s influence on macrophagesmetabolic reprogramming in tumorsPI3K/Akt pathway in cancerstrategies to target lactate in cancer therapytumor microenvironment and lactylationWarburg effect in cancer metabolism