Chronic stress promotes breast cancer progression via MTA2 lactylation-mediated destabilization of the NuRD complex

Chronic stress is associated with increased risk of breast cancer metastasis and poor clinical outcomes; however, the underlying mechanisms remain incompletely understood. Here, we demonstrated that chronic stress elevates lactate levels in the tumor microenvironment, thereby promoting lactylation of metastasis associated 1 family member 2 (MTA2) at lysine 460. Mechanistically, chronic stress not only enhances lactate metabolism within the tumor microenvironment, providing sufficient substrate for lactylation, but also activates the β2-adrenergic receptor (β2-AR)/PKA signaling axis, leading to P300 phosphorylation and cooperatively facilitating MTA2 lactylation. This modification weakens the interaction between MTA2 and RBBP7, resulting in destabilization of the nucleosome remodelling and histone deacetylase (NuRD) complex and impaired transcriptional repression. This is accompanied by increased H3K9 acetylation and upregulation of genes associated with both tumor progression and metastasis, including MMP16, NRP1, and VCAM1. Importantly, a cell-penetrating peptide specifically targeting MTA2 lactylation effectively inhibits breast tumor growth and reduces lung metastatic burden in chronic stress models. Together, our findings identify protein lactylation, especially that of MTA2, as a key regulatory event in chronic stress-induced tumor progression, providing new insights into the link between tumor epigenetics and chronic stress, and suggesting a potential biomarker and therapeutic target for prognostic assessment and clinical intervention in breast cancer patients under chronic stress.