Primary tumor-derived lactate primes prostate cancer cells for a dormant fate

The metastatic outcome depends on the state of disseminated cancer cells (DCCs) leading to overt metastasis or undergoing dormancy. Before distant organ colonization, primary tumor microenvironment may shape the decision between proliferation and dormancy. Here, we identify lactic acid (LA), a highly abundant environmental metabolite at the primary site in prostate cancer (PCa), as a key inducer of dormant state. LA-uploading PCa cells undergo a proliferation delay, associated with stemness, therapy tolerance, and invasiveness through the nuclear receptor subfamily 2 group F member 1 (COUP-TF1/NR2F1) activation. These traits rely on LA-driven accumulation of lipid droplets (LDs), which serve as reservoirs of lipid-derived acetyl moieties essential for histone acetylation. Notably, the epigenetic reader BRD4 is essential for COUP-TF1 expression and for establishing and maintaining dormancy. In metastatic sites, where LA levels are low, dormant features are lost, allowing DCCs to support metastatic growth. Last, targeting LA-mediated LD formation or BRD4 activation prevents dormancy entry, reducing PCa cell adaptability and increasing vulnerability to antiproliferative therapies.