Lactylation-mediated remodelling of the breast cancer microenvironment: single-cell multidimensional analysis and prognostic model construction

BackgroundThe breast cancer tumour microenvironment (TME) exhibits marked cellular and metabolic heterogeneity that contributes to disease progression and therapeutic resistance. Lactylation, a lactate-derived post-translational modification, has emerged as a potential link between metabolic reprogramming and tumour-associated transcriptional and immune changes.

However, its cell-type distribution and clinical relevance in breast cancer remain incompletely defined.MethodsWe integrated 26 scRNA-seq samples spanning ER+, HER2+, and triple-negative breast cancer (TNBC), comprising 98,572 cells. A literature-curated lactylation-related transcriptional module score was calculated using AddModuleScore, and epithelial cells were stratified into high- and low-score states for downstream analyses.

Candidate genes were prioritised by integrating single-cell differential expression, a curated lactylation-related gene pool, and tumour-associated expression changes in TCGA-BRCA. A 14-gene prognostic model was developed using LASSO-Cox regression in TCGA-BRCA and externally validated in GSE20685 and METABRIC.

Additional analyses evaluated associations with immune infiltration, somatic alterations, and predicted drug sensitivity. Functional relevance was explored through CALR knockdown in breast cancer cells and xenograft assays.ResultsSingle-cell analysis identified six major cell populations and revealed marked subtype-related heterogeneity.