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 energises tumours 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 synthesising 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 metabolise glucose into lactate even with oxygen present—creates an acidic tumour 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 emphasise the critical need to investigate lactate-driven mechanisms to develop next-generation therapies.

Published in Cancer Biology & Medicine, researchers from Nanjing Medical University and Zhejiang University systematically analysed over 120 recent studies on lactate metabolism in breast cancer.

Their review identifies lactylation—a novel post-translational modification—as a key driver of tumour progression through epigenetic regulation.

The team details how lactate-induced modifications alter protein function in both cancer cells and immune components within the tumour 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-tumour pathways: (1) Acidifying the microenvironment to promote invasion via matrix metalloproteinases; (2) Inducing immunosuppression through PD-L1 upregulation and M2 macrophage polarisation; (3) Stimulating angiogenesis via VEGF signalling.

The newly characterised lactylation process modifies both histones (e.g., H3K18la, H4K12la) and critical tumour suppressors like p53, with AARS1 enzyme identified as the primary mediator.

In TNBC, lactylation silences tumour 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% tumour 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 tumour 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 tumours by simultaneously modifying cancer cell behaviour 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

Source: China Anti-Cancer Association