Lactylation drives tumor progression and immune evasion in triple negative breast cancer

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. 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."

Dr. Jian Wu, corresponding author

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.