LDHB Deficiency in Fibroblasts Induces Lactate-Mediated Inflammatory Reprogramming that Promotes Breast Cancer Metastasis.

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and often undergo metabolic reprogramming. Metabolic shifts within CAFs can influence cancer cell behavior. In this study, we revealed that the loss of lactate dehydrogenase B (LDHB) in CAFs drives a metabolic shift that significantly enhances breast cancer metastasis. LDHB loss in CAFs drove a shift towards an inflammatory fibroblast phenotype. Mechanistically, LDHB deficiency led to lactate accumulation, which disrupted the interaction between dual specificity phosphatase 16 (DUSP16) and p38, causing sustained p38 activation. Persistent p38 signaling reprogrammed CAFs into an inflammatory phenotype characterized by abundant secretion of the chemokine CXCL8, which in turn enhanced metastasis of breast cancer cells. In summary, these findings identify LDHB as a key metabolic regulator in CAFs and provide insights into how metabolic reprogramming promotes the inflammatory, pro-metastatic phenotype of CAFs, highlighting activating LDHB as a potential strategy for limiting cancer metastasis.