L-Lactate reprograms tumor-associated macrophages to drive pancreatic cancer progression via BCL3 lactylation

Summary Metabolic reprogramming fuels pancreatic ductal adenocarcinoma (PDAC) malignancy, creating a nutrient-deprived and waste-rich microenvironment. How this extreme metabolic pressure dictates the phenotypic remodeling of infiltrating immune cells remains largely unclear. Metabolomic profiling of PDAC reveals that robust tumor glycolysis proceeds without a commensurate accumulation of extracellular lactate. Integrated single-cell profiling and tissue multiplex immunofluorescence demonstrate that tumor-associated macrophages (TAMs) act as the primary consumers of tumor-secreted lactate. The uptake of L-lactate directs macrophages toward a pro-tumorigenic state through site-specific L-lactylation of the transcriptional co-regulator BCL3 at lysine 21 (K21). Functioning as a molecular switch, K21 lactylation triggers BCL3 nuclear translocation and enhances its interaction with the NF-κB p50 subunit. The ensuing BCL3-p50 complex competitively displaces the pro-inflammatory p65 subunit, rewiring the transcriptional output to suppress inflammation and enforce tumor-supporting networks. In vivo , macrophage-specific expression of a lactylation-deficient BCL3 mutant (K21R) abolishes lactate-driven phenotypic shifts and restricts tumor growth. Clinically, a BCL3-lactylated macrophage signature spatially correlates with CD8 + T cell exclusion and predicts poor patient survival, providing a strong rationale for targeting the BCL3-lactylation axis to reverse TAM-driven PDAC progression.