A lactate-fatty acid loop drives prostate cancer bone colonization by mediating metabolic interplay between tumor cells and osteoblasts

Bone metastasis is the major cause of morbidity and mortality in advanced prostate cancer, yet current therapies provide only limited clinical benefit. Here, we show that prostate cancer cells metabolically adapt to the bone microenvironment by utilizing bone-cell-derived lactate as an alternative nutrient source. Beyond fueling oxidative phosphorylation, lactate serves as carbon source for fatty acid synthesis. Among the resulting lipid products, oleic acid is secreted to reward osteoblast, establishing a reciprocal metabolic interplay that supports both tumor progression and pathological bone formation. Mechanistically, we identify MCT1 as the essential transporter mediating lactate uptake in bone-colonizing tumor cells. MCT1 expression is coordinately regulated by NFAT signaling and extracellular glucose availability at both transcriptional and post-translational levels. Genetic deletion and pharmacological inhibition of MCT1 markedly suppresses prostate tumor growth in bone. Together, these findings uncover a lactate-driven metabolic crosstalk, identifying MCT1 as a promising therapeutic target for prostate cancer bone metastasis.